NTR domain, WFIKKN subfamily; WFIKKN proteins contain a C-terminal NTR domain and are putative secreted proteins which may be multivalent protease inhibitors that act on serine proteases as well as metalloproteases. Human WFIKKN and a related protein sharing the same domain architecture were observed to have distinct tissue expression patterns. WFIKKN is also referred to as growth and differentiation factor-associated serum protein-1 (GASP-1). It inhibits the activity of mature myostatin, a specific regulator of skeletal muscle mass and a member of the TGFbeta superfamily.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 16751923 427 ALSLCRSDFAIVGRLTEVLEEPEaaGGIARVALEDVLKDDKMGLKFLGTKYLEVTLSGMDWACPCPNMTAGDGPLVIMGE 506
Cdd:cd03575   1 VPSLCRSDFAIVGRLTELTEELD--SGHARVTLEEVLKDEKMGLKFFGTEPLEVTLLNMDWSCPCPNITAGEGPLIIMGD 78

                        90       100       110
                ....*....|....*....|....*....|.
gi 16751923 507 VRDGVAVLDAGSYVRAASEKRVKKILELLEK 537
Cdd:cd03575  79 VHDGMAVLQPDSYVRASSERRVRKLREVLHK 109

second Kunitz domain of WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing proteins; This subfamily includes WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing protein 1 (WFIKKN1, WFKN1), WFIKKN2 (WFKN2), and similar proteins. WFIKKN proteins are protease inhibitors that contain two distinct Kunitz-type protease inhibitor domains. They may have serine protease- and metalloprotease-inhibitor activity. This model represents the second Kunitz (KU2) domain, which has been shown to inhibit trypsin, but not chymotrypsin, elastase, plasmin, pancreatic kallikrein, lung tryptase, plasma kallikrein, thrombin, urokinase or tissue plasminogen activator. However, the inhibition constant of this domain for bovine trypsin is about five orders of magnitudes lower than that of bovine pancreatic trypsin inhibitor (BPTI) for trypsin. This could be due to unfavorable side-chain conformation of a tryptophan at P2' site which is incompatible with a trypsin complex; typical trypsin inhibitors of the Kunitz family feature a tyrosine residue or other less bulky residues at this site. The structure of KU2 is similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 16751923 358 ACVLPAVQGPCRGWEPRWAYSPLLQQCHPFVYGGCEGNGNNFHSRESCEDACP 410
Cdd:cd22606   1 ICSLPAVQGPCKAWEPRWAYNSLLKQCQSFVYGGCEGNENNFESKEACEDACP 53

Kazal type serine protease inhibitors and follistatin-like domains. Kazal inhibitors inhibit serine proteases, such as, trypsin, chyomotrypsin, avian ovomucoids, and elastases. The inhibitory domain has one reactive site peptide bond, which serves the cognate enzyme as substrate. The reactive site peptide bond is a combining loop which has an identical conformation in all Kazal inhibitors and in all enzyme/inhibitor complexes. These Kazal domains (small hydrophobic core of alpha/beta structure with 3 to 4 disulfide bonds) often occur in tandem arrays. Similar domains are also present in follistatin (FS) and follistatin-like family members, which play an important role in tissue specific regulation. The FS domain consists of an N-terminal beta hairpin (FOLN/EGF-like domain) and a Kazal-like domain and has five disulfide bonds. Although the Kazal-like FS substructure is similar to Kazal proteinase inhibitors, no FS domain has yet been shown to be a proteinase inhibitor. Follistatin-like family members include SPARC, also known as, BM-40 or osteonectin, the Gallus gallus Flik protein, as well as, agrin which has a long array of FS domains. The kazal-type inhibitor domain has also been detected in an extracellular loop region of solute carrier 21 (SLC21) family members (organic anion transporters) , which may regulate the specificity of anion uptake. The distant homolog, Ascidian trypsin inhibitor, is included in this CD.

                        10        20        30
                ....*....|....*....|....*....|....*.
gi 16751923 120 CEKEPSFTCASDGLTYYNRCYMDAEACLRGLHLHIV 155
Cdd:cd00104   1 CPKEYDPVCGSDGKTYSNECHLGCAACRSGRSITVA 36

NTR domain, WFIKKN subfamily; WFIKKN proteins contain a C-terminal NTR domain and are putative secreted proteins which may be multivalent protease inhibitors that act on serine proteases as well as metalloproteases. Human WFIKKN and a related protein sharing the same domain architecture were observed to have distinct tissue expression patterns. WFIKKN is also referred to as growth and differentiation factor-associated serum protein-1 (GASP-1). It inhibits the activity of mature myostatin, a specific regulator of skeletal muscle mass and a member of the TGFbeta superfamily.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 16751923 427 ALSLCRSDFAIVGRLTEVLEEPEaaGGIARVALEDVLKDDKMGLKFLGTKYLEVTLSGMDWACPCPNMTAGDGPLVIMGE 506
Cdd:cd03575   1 VPSLCRSDFAIVGRLTELTEELD--SGHARVTLEEVLKDEKMGLKFFGTEPLEVTLLNMDWSCPCPNITAGEGPLIIMGD 78

                        90       100       110
                ....*....|....*....|....*....|.
gi 16751923 507 VRDGVAVLDAGSYVRAASEKRVKKILELLEK 537
Cdd:cd03575  79 VHDGMAVLQPDSYVRASSERRVRKLREVLHK 109

second Kunitz domain of WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing proteins; This subfamily includes WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing protein 1 (WFIKKN1, WFKN1), WFIKKN2 (WFKN2), and similar proteins. WFIKKN proteins are protease inhibitors that contain two distinct Kunitz-type protease inhibitor domains. They may have serine protease- and metalloprotease-inhibitor activity. This model represents the second Kunitz (KU2) domain, which has been shown to inhibit trypsin, but not chymotrypsin, elastase, plasmin, pancreatic kallikrein, lung tryptase, plasma kallikrein, thrombin, urokinase or tissue plasminogen activator. However, the inhibition constant of this domain for bovine trypsin is about five orders of magnitudes lower than that of bovine pancreatic trypsin inhibitor (BPTI) for trypsin. This could be due to unfavorable side-chain conformation of a tryptophan at P2' site which is incompatible with a trypsin complex; typical trypsin inhibitors of the Kunitz family feature a tyrosine residue or other less bulky residues at this site. The structure of KU2 is similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 16751923 358 ACVLPAVQGPCRGWEPRWAYSPLLQQCHPFVYGGCEGNGNNFHSRESCEDACP 410
Cdd:cd22606   1 ICSLPAVQGPCKAWEPRWAYNSLLKQCQSFVYGGCEGNENNFESKEACEDACP 53

first Kunitz domain of WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing proteins; This subfamily includes WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing protein 1 (WFIKKN1, WFKN1), WFIKKN2 (WFKN2), and similar proteins. WFIKKN proteins are protease inhibitors that contain two distinct Kunitz-type protease inhibitor domains. They may have serine protease- and metalloprotease-inhibitor activity. This model represents the first Kunitz domain that is similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 16751923 298 ECLPDVQACTGPTspHLVLWHYDPQRGGCMTFPARGCDGAARGFETYEACQQAC 351
Cdd:cd22605   1 ECLKEPDREDCGE--EQVRWYFDAKRGNCFTFTYGGCDGNRNHFETYEECRLAC 52

Immunoglobulin domain; This family contains immunoglobulin-like domains.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 16751923   185 PPALYSSPSPQAVQVGGTASLHCDVSGRPPPAVTWEKQSHQRENLIMRPDQMYGNVvvtsiGQLVLYNARPEDAGLYTCT 264
Cdd:pfam13927   1 KPVITVSPSSVTVREGETVTLTCEATGSPPPTITWYKNGEPISSGSTRSRSLSGSN-----STLTISNVTRSDAGTYTCV 75

                  ...
gi 16751923   265 ARN 267
Cdd:pfam13927  76 ASN 78

Kazal type serine protease inhibitors and follistatin-like domains. Kazal inhibitors inhibit serine proteases, such as, trypsin, chyomotrypsin, avian ovomucoids, and elastases. The inhibitory domain has one reactive site peptide bond, which serves the cognate enzyme as substrate. The reactive site peptide bond is a combining loop which has an identical conformation in all Kazal inhibitors and in all enzyme/inhibitor complexes. These Kazal domains (small hydrophobic core of alpha/beta structure with 3 to 4 disulfide bonds) often occur in tandem arrays. Similar domains are also present in follistatin (FS) and follistatin-like family members, which play an important role in tissue specific regulation. The FS domain consists of an N-terminal beta hairpin (FOLN/EGF-like domain) and a Kazal-like domain and has five disulfide bonds. Although the Kazal-like FS substructure is similar to Kazal proteinase inhibitors, no FS domain has yet been shown to be a proteinase inhibitor. Follistatin-like family members include SPARC, also known as, BM-40 or osteonectin, the Gallus gallus Flik protein, as well as, agrin which has a long array of FS domains. The kazal-type inhibitor domain has also been detected in an extracellular loop region of solute carrier 21 (SLC21) family members (organic anion transporters) , which may regulate the specificity of anion uptake. The distant homolog, Ascidian trypsin inhibitor, is included in this CD.

                        10        20        30
                ....*....|....*....|....*....|....*.
gi 16751923 120 CEKEPSFTCASDGLTYYNRCYMDAEACLRGLHLHIV 155
Cdd:cd00104   1 CPKEYDPVCGSDGKTYSNECHLGCAACRSGRSITVA 36

BPTI/Kunitz family of serine protease inhibitors; Serine protease inhibitors. One member of the family is encoded by an alternatively-spliced form of Alzheimer's amyloid beta-protein.

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*
gi 16751923    307 TGPTSPHLVLWHYDPQRGGCMTFPARGCDGAARGFETYEACQQAC 351
Cdd:smart00131   9 TGPCGGSIPRYYYDPETGTCEPFTYGGCGGNANNFESLEECERTC 53

Kazal type serine protease inhibitors; Kazal type serine protease inhibitors and follistatin-like domains.

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|
gi 16751923    116 CRDRCEKEPSFTCASDGLTYYNRCYMDAEACLRGLHLHIV 155
Cdd:smart00280   2 CPEACPREYDPVCGSDGVTYSNECHLCKAACESGKSIEVK 41

NTR domain, WFIKKN subfamily; WFIKKN proteins contain a C-terminal NTR domain and are putative secreted proteins which may be multivalent protease inhibitors that act on serine proteases as well as metalloproteases. Human WFIKKN and a related protein sharing the same domain architecture were observed to have distinct tissue expression patterns. WFIKKN is also referred to as growth and differentiation factor-associated serum protein-1 (GASP-1). It inhibits the activity of mature myostatin, a specific regulator of skeletal muscle mass and a member of the TGFbeta superfamily.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 16751923 427 ALSLCRSDFAIVGRLTEVLEEPEaaGGIARVALEDVLKDDKMGLKFLGTKYLEVTLSGMDWACPCPNMTAGDGPLVIMGE 506
Cdd:cd03575   1 VPSLCRSDFAIVGRLTELTEELD--SGHARVTLEEVLKDEKMGLKFFGTEPLEVTLLNMDWSCPCPNITAGEGPLIIMGD 78

                        90       100       110
                ....*....|....*....|....*....|.
gi 16751923 507 VRDGVAVLDAGSYVRAASEKRVKKILELLEK 537
Cdd:cd03575  79 VHDGMAVLQPDSYVRASSERRVRKLREVLHK 109

second Kunitz domain of WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing proteins; This subfamily includes WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing protein 1 (WFIKKN1, WFKN1), WFIKKN2 (WFKN2), and similar proteins. WFIKKN proteins are protease inhibitors that contain two distinct Kunitz-type protease inhibitor domains. They may have serine protease- and metalloprotease-inhibitor activity. This model represents the second Kunitz (KU2) domain, which has been shown to inhibit trypsin, but not chymotrypsin, elastase, plasmin, pancreatic kallikrein, lung tryptase, plasma kallikrein, thrombin, urokinase or tissue plasminogen activator. However, the inhibition constant of this domain for bovine trypsin is about five orders of magnitudes lower than that of bovine pancreatic trypsin inhibitor (BPTI) for trypsin. This could be due to unfavorable side-chain conformation of a tryptophan at P2' site which is incompatible with a trypsin complex; typical trypsin inhibitors of the Kunitz family feature a tyrosine residue or other less bulky residues at this site. The structure of KU2 is similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 16751923 358 ACVLPAVQGPCRGWEPRWAYSPLLQQCHPFVYGGCEGNGNNFHSRESCEDACP 410
Cdd:cd22606   1 ICSLPAVQGPCKAWEPRWAYNSLLKQCQSFVYGGCEGNENNFESKEACEDACP 53

first Kunitz domain of WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing proteins; This subfamily includes WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing protein 1 (WFIKKN1, WFKN1), WFIKKN2 (WFKN2), and similar proteins. WFIKKN proteins are protease inhibitors that contain two distinct Kunitz-type protease inhibitor domains. They may have serine protease- and metalloprotease-inhibitor activity. This model represents the first Kunitz domain that is similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....
gi 16751923 298 ECLPDVQACTGPTspHLVLWHYDPQRGGCMTFPARGCDGAARGFETYEACQQAC 351
Cdd:cd22605   1 ECLKEPDREDCGE--EQVRWYFDAKRGNCFTFTYGGCDGNRNHFETYEECRLAC 52

Kunitz domain 2 of hepatocyte growth factor activator inhibitor-1 (HAI1); This model includes Kunitz domain 2 (KD2) of hepatocyte growth factor activator inhibitor type 1 (HAI-1 or HAI1, also known as Kunitz-type protease inhibitor 1), a membrane-bound multidomain protein essential to the integrity of the basement membrane during placental development. HAI-1 contains an extracellular region and several internal domains that include two Kunitz domains separated in sequence but spatially closed to each other, and their interdomain interactions have evolved to stimulate the inhibitory activity of an integrated Kunitz. While the Kunitz domain 1 (KD1) is the major inhibitory domain of HAI-1 and involved in auto-inhibition of the extracellular region via steric blockage of its active site in the HAI-1 compact tertiary structure, studies show that deletion of HAI-1 Kunitz domain 2 (KD2) and the extracellular region enhanced inhibition of matriptase. HAI-1 KD2 has been shown to have potent inhibitory activity against trypsin, but it cannot inhibit hepatocyte growth factor activator (HGFA), and matriptase. HAI-1 is also important in maintaining postnatal homeostasis in many tissues, including keratinization of the epidermis, hair development, colonic epithelium integrity, proliferation and cell fate of neural progenitor cells, and tissue injury and repair. The interaction between HAI-1 and matriptase is critical for tissue morphogenesis and cellular biology. HAI-1:matriptase ratio imbalance results in tumorigenesis; slight overexpression of matriptase relative to HAI-1 causes spontaneous squamous cell carcinoma, a phenotype that can be effectively reversed back to wild type by additional expression of HAI-1, indicating the need for a tight functional relationship between the two to maintain homeostasis. The structure of KD2 is similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 16751923 359 CVLPAVQGPCRGWEPRWAYSPLLQQCHPFVYGGCEGNGNNFHSRESCEDAC 409
Cdd:cd22624   2 CTEPPVTGPCRASFTRWYYDPLSRKCHRFTYGGCDGNENNFETEDECMETC 52

Kunitz domain 1 (KD1) of tissue factor pathway inhibitor 2 (TFPI2) and similar proteins; This model represents the Kunitz-type domain 1 (KD1) of tissue factor pathway inhibitor 2 (TFPI2 or TFPI-2) and similar proteins. TFPI2 exhibits inhibitory activity primarily toward trypsin, plasmin, and factor VIIa (FVIIa)/tissue factor (TF) via its KD1. It is believed to be the major inhibitor of plasmin in the extracellular matrix (ECM) but has little inhibitory activity toward urokinase-type plasminogen activator, tissue-type plasminogen activator, or thrombin. TFPI2 specifically inhibits the proteases via the P1 arginine residue in KD1. The TFPI2 domains KD2 and KD3 appear to have no discernible inhibitory activity and may serve to bind to nearby proteins to localize TFPI2 in the ECM. Structure studies of KD1 complexed with proteases may help in the development of specific and potent KD1 domain protein that may have a large pharmacologic impact in preventing tumor metastasis, retinal degeneration, and degradation of collagen in the ECM. The structure of this domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 16751923 357 DACVLPAVQGPCRGWEPRWAYSPLLQQCHPFVYGGCEGNGNNFHSRESCEDAC 409
Cdd:cd22616   3 EICLLPPDEGPCRALIPRYYYDRYTQTCREFSYGGCEGNANNFESLEDCEKTC 55

Kunitz domain 1 of hepatocyte growth factor activator inhibitor-1 (HAI-1); This model includes Kunitz domain 1 (KD1) of hepatocyte growth factor activator inhibitor type 1 (HAI1 or HAI-1, also known as Kunitz-type protease inhibitor 1), a membrane-bound multidomain protein essential to the integrity of the basement membrane during placental development. HAI-1 contains an extracellular region and several internal domains that include two Kunitz domains separated in sequence but spatially closed to each other, and their interdomain interactions have evolved to stimulate the inhibitory activity of an integrated Kunitz. KD1, the major inhibitory domain of HAI-1, is involved in auto-inhibition of the extracellular region via steric blockage of its active site in the HAI-1 compact tertiary structure; presence of the target protease causes changes in the HAI-1 structure to an extended conformation. HAI-1 has been shown to inhibit several serine proteases such as matripase, hepsin, trypsin, hepatocyte growth factor activator (HGFA), and prostasin. It is also important in maintaining postnatal homeostasis in many tissues, including keratinization of the epidermis, hair development, colonic epithelium integrity, proliferation and cell fate of neural progenitor cells, and tissue injury and repair. The interaction between HAI-1 and matriptase is critical for tissue morphogenesis and cellular biology. HAI-1:matriptase ratio imbalance results in tumorigenesis; slight overexpression of matriptase relative to HAI-1 causes spontaneous squamous cell carcinoma, a phenotype that can be effectively reversed back to wild type by additional expression of HAI-1, indicating the need for a tight functional relationship between the two to maintain homeostasis. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 16751923 359 CVLPAVQGPCRGWEPRWAYSPLLQQCHPFVYGGCEGNGNNFHSRESCEDAC 409
Cdd:cd22623   6 CLAPKKVGPCRGSFPRWHYNAASGKCEEFVFGGCKGNKNNYLSEEECLSAC 56

Immunoglobulin I-set domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 16751923   192 PSPQAVQVGGTASLHCDVSGRPPPAVTWEKQSHQrenliMRPDQMYGNVVVTSIGQLVLYNARPEDAGLYTCTARNAAGL 271
Cdd:pfam07679   7 PKDVEVQEGESARFTCTVTGTPDPEVSWFKDGQP-----LRSSDRFKVTYEGGTYTLTISNVQPDDSGKYTCVATNSAGE 81

                  ....*....
gi 16751923   272 LRADFPLSV 280
Cdd:pfam07679  82 AEASAELTV 90

third Kunitz domain of Carboxypeptidase Inhibitor SmCI and similar domains; This group includes Sabellastarte magnifica carboxypeptidase inhibitor (SmCI), Bombyx mori cocoon shell-associated trypsin inhibitor (CSTI), Bombus terrestris Kunitz-type serine protease inhibitor Bt-KTI, and similar domains. SmCI is a tri-domain BPTI-Kunitz inhibitor capable of inhibiting serine proteases and A-like metallocarboxypeptidases. While the BPTI-Kunitz family of proteins includes voltage gated channel blockers and inhibitors of serine proteases, SmCI is the only BPTI-Kunitz protein capable of inhibiting metallocarboxypeptidases. Binding studies show that SmCI is able to bind three trypsin molecules under saturating conditions, but only one elastase interacts with the inhibitor. Additionally, SmCI can bind serine proteases and carboxypeptidases at the same time (at least in the ratio 1:1:1), thus becoming the first protease inhibitor that simultaneously blocks these two mechanistic classes of enzymes. CSTI and Bt-KTI are single Kunitz domain proteins that inhibit trypsin; in addition, Bt-KTI also inhibits plasmin. This model contains the third Kunitz domain of SmCI which has a structure similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 16751923 357 DACVLPAVQGPCRGWEPRWAYSPLLQQCHPFVYGGCEGNGNNFHSRESCEDAC 409
Cdd:cd22603   1 EDCLLPSETGPCKGSFPRYYYDKETGKCKEFIYGGCQGNANNFETKEECERAC 53

Kunitz-type actitoxins such as Anemonia viridis U-actitoxin-Avd3l, and similar proteins; This model includes the Kunitz-type actitoxins such as Anemonia viridis U-actitoxin-Avd3l (also called U-AITX-Avd3l or AsKC9), Anthopleura elegantissima KappaPI-actitoxin-Ael3a (also called KappaPI-AITX-Ael3a or Kunitz-type serine protease inhibitor APEKTx1) and Anthopleura aff. xanthogrammica PI-actitoxin-Axm2b (also called PI-AITX-Axm2b or Kunitz-type proteinase inhibitor AXPI-II). U-AITX-Avd3l and KappaPI-AITX-Ael3a are dual-function toxins that inhibit both the serine protease trypsin and voltage-gated potassium channels Kv1.2/KCNA2. These proteins are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 16751923 359 CVLPAVQGPCRGWEPRWAYSPLLQQCHPFVYGGCEGNGNNFHSRESCEDAC 409
Cdd:cd22633   5 CLLPKDVGGCRARFPRYYYNSSTRRCEKFRYGGCGGNANNFHTLEECEKVC 55

second Kunitz domain of bikunin and similar proteins; This subfamily includes the C-terminal domain of bikunin (also known as inter-alpha-trypsin inhibitor light chain (ITI-LC) or urinary trypsin inhibitor), a plasma protease inhibitor, that is associated with inflammation and stabilizes the extracellular matrix. Bikunin is encoded together with alpha-1-microglobulin (A1M) by an alpha-1-microglobulin/bikunin precursor (AMBP) gene that is tightly controlled by several hepatocyte-enriched nuclear (HEN) factors, and cleaved by a furin-like protease that releases the two mature molecules. Bikunin is a Kunitz-type serine protease inhibitor, found in vertebrate serum and urine, modified by a chondroitin sulfate (CS) chain. The structures of these toxins are similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds. Bikunin contains two Kunitz domains; this model represents the second repeat.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 16751923 357 DACVLPAVQGPCRGWEPRWAYSPLLQQCHPFVYGGCEGNGNNFHSRESCEDAC 409
Cdd:cd22597   2 AACRLPIVPGPCKGFVDLWAFDAVQGKCVPFSYGGCQGNGNKFYSEKECEEYC 54

Kunitz-type domain from the alpha3 chain of human type VI collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha3 chain of type VI collagen (collagen alpha 3(VI) chain), encoded by COL6A3 gene. Collagen VI is a widely expressed member of the triple helix-containing protein superfamily of collagens and forms beaded microfibrils that anchor large interstitial structures. Immediately after fibril formation, the Kunitz domain can be cleaved off. Mutations in the alpha1, alpha2, and alpha3 chains of collagen VI cause myopathies ranging from the severe Ullrich congenital muscular dystrophy to the milder Bethlem myopathy, including intermediate forms. Early onset isolated dystonia, a neurological disease, has been shown to be caused by mutations in the alpha3 chain. Findings also indicated potential associations between COL6A3 polymorphisms and lung cancer risk. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 16751923 357 DACVLPAVQGPCRGWEPRWAYSPLLQQCHPFVYGGCEGNGNNFHSRESCEDAC 409
Cdd:cd22629   1 DICKLPKDEGTCRDFVLKWYYDPETKSCARFWYGGCGGNENRFDSQEECEKVC 53

chymotrypsin inhibitor SCI-I_III-like; This model includes the Kunitz-type chymotrypsin inhibitors SCI-III and SCI-I, and similar proteins in insects. SCI-III and SCI-I inhibit chymotrypsin, avoiding the accidental chymotrypsin-mediated activation of prophenoloxidase. This enzyme is required by the insect immune system to produce melanin which is used to engulf foreign objects. This subfamily also includes Kunitz-type male accessory gland peptide with protease inhibitory activity, synthesized and secreted by male accessory glands of Drosophila funebris; it may play a role as an acrosin inhibitor involved in reproduction. These proteins are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 16751923 347 CQQACARGPGDAcvlpavqGPCRGWEPRWAYSPLLQQCHPFVYGGCEGNGNNFHSRESCEDAC 409
Cdd:cd22634   2 CGQPHSLGGGDG-------ISCFAYIPSWSYNPDKNECEEFIYGGCGGNDNRFSTKAECEQKC 57

venom Kunitz-type proteins such as textilinin, BF9 and PILP; This group includes toxins isolated from snake venoms, such as textilinin, vestiginin, spermatin, mulgin, venom basic protease inhibitor IX (BF9), and protease inhibitor-like protein (PILP), among others. Pseudonaja textilis textilinin-1 is a Kunitz-type serine protease inhibitor that binds to and blocks the activity of a range of serine proteases, including plasmin and trypsin. Ability of testilinin to inhibit plasmin, a protease involved in fibrinolysis, raises the possibility that it may be used as an alternative to aprotinin (Trasylol), which is a systemic antibleeding agent in surgery. Also included is the Bungarus fasciatus fraction IX (BF9), a chymotrypsin inhibitor that binds chymotrypsin but not trypsin. Protease inhibitor-like proteins PILP-1 and PILP-2 show weak binding and inhibition of matrix metalloproteinase-2 (MMP-2) and show an activity in inhibiting migration and invasion of neuroblastoma; they do not inhibit chymotrypsin or trypsin. The structures of these toxins are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 16751923 359 CVLPAVQGPCRGWEPRWAYSPLLQQCHPFVYGGCEGNGNNFHSRESCEDAC 409
Cdd:cd22594   5 CELPADPGPCNAYKPAFYYNPASHKCLEFIYGGCGGNANNFKTIDECHRTC 55

Fourth immunoglobulin domain of the Drosophila melanogaster Dscam protein, and similar domains; a member of the I-set of IgSF domains; The members here are composed of the fourth immunoglobulin domain of the Drosophila melanogaster Down syndrome cell adhesion molecule (DSCAM) protein and similar proteins. Down syndrome cell adhesion molecule (DSCAM) is a cell adhesion molecule that plays critical roles in neural development, including axon guidance and branching, axon target recognition, self-avoidance and synaptic formation. DSCAM belongs to the immunoglobulin superfamily and contributes to defects in the central nervous system in Down syndrome patients. Vertebrate DSCAMs differ from Drosophila Dscam1 in that they lack the extensive alternative splicing that occurs in the insect gene. Drosophila melanogaster Dscam has 38,016 isoforms generated by the alternative splicing of four variable exon clusters, which allows every neuron in the fly to display a distinctive set of Dscam proteins on its cell surface. Drosophila Dscam1 is a cell-surface protein that plays important roles in neural development and axon tiling of neurons. It is shown that thousands of isoforms bind themselves through specific homophilic (self-binding) interactions, a process which mediates cellular self-recognition. Drosophila Dscam2 is also alternatively spliced and plays a key role in the development of two visual system neurons, monopolar cells L1 and L2. This group is a member of the I-set Ig domains, having A-B-E-D strands in one beta-sheet and A'-G-F-C-C' in the other. Like the V-set Ig domains, members of the I-set have a discontinuous A strand but lack a C" strand.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 16751923 185 PPALYSSPSPQAVQVGGTASLHCDVSGRPPPAVTWE------KQSHQRenlimrpdqMYGNvVVTSIGQLVLY----NAR 254
Cdd:cd20956   1 APVLLETFSEQTLQPGPSVSLKCVASGNPLPQITWTldgfpiPESPRF---------RVGD-YVTSDGDVVSYvnisSVR 70

                        90
                ....*....|....*.
gi 16751923 255 PEDAGLYTCTARNAAG 270
Cdd:cd20956  71 VEDGGEYTCTATNDVG 86

Kunitz-type domain from the alpha1 chain of type VII collagen, and similar proteins; This model includes the Kunitz-type domain from the alpha1 chain of type VII collagen (collagen alpha-1(VII) chain also called long-chain collagen or LC collagen) and similar proteins. LC collagen, encoded by the COL7A1 gene, is a stratified squamous epithelial basement membrane protein that forms anchoring fibrils which may contribute to epithelial basement membrane organization and adherence by interacting with extracellular matrix (ECM) proteins such as type IV collagen. So far, over 800 COL7A1 mutations have been reported, including missense, nonsense, splicing, insertion, and deletion mutations which to varying degrees leads to deficiency of type VII collagen. Epidermolysis bullosa acquisita (EBA) is an autoimmune acquired blistering skin disease resulting from autoantibodies to type VII collagen. The COL7A1 protein contains a Kunitz domain, the deactivation of which induces tumorigenesis. This domain is similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 16751923 357 DACVLPAVQGPCRGWEPRWAYSPLLQQCHPFVYGGCEGNGNNFHSRESCEDAC 409
Cdd:cd22627   1 DPCLLPMDEGSCSDYTLLWYYHQKAGECRPFVYGGCGGNANRFSSKEDCELRC 53

second Kunitz domain of Rhipicephalus microplus boophilin and similar proteins; This group includes venom serine protease inhibitors such as Rhipicephalus microplus and Ixodes scapularis boofilin, among others. Boophilin prevents blood clot formation to allow successful feeding and digestion through its inhibition activity of thrombin and other host anticoagulating factors like kallikrein, coagulation factor VII, or plasmin; it interacts with the host thrombin and trypsin. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds. Rhipicephalus microplus boophilin contains two Kunitz domains; this model represents the second repeat.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 16751923 358 ACVLPAVQGPCRGWEPRWAYSPLLQQCHPFVYGGCEGNGNNFHSRESCEDAC 409
Cdd:cd22600   1 GCKPAAESGLCAAYLERWFFNVTTGACETFVYGGCGGNANNYKSQEECELAC 52

Fourth immunoglobulin (Ig)-like domain in Robo (roundabout) receptors; member of the I-set of Ig superfamily (IgSF) domains; Members here are composed the fourth immunoglobulin (Ig)-like domain in Robo (roundabout) receptors. Robo receptors play a role in the development of the central nervous system (CNS), and are receptors of Slit protein. Slit is a repellant secreted by the neural cells in the midline. Slit acts through Robo to prevent most neurons from crossing the midline from either side. Three mammalian Robo homologs (Robo1, Robo2, Robo3), and three mammalian Slit homologs (Slit-1, Slit-2, Slit-3), have been identified. Commissural axons, which cross the midline, express low levels of Robo; longitudinal axons, which avoid the midline, express high levels of Robo. Robo1, Robo2, and Robo3 are expressed by commissural neurons in the vertebrate spinal cord and Slit-1, Slit-2, and Slit-3 are expressed at the ventral midline. Robo-3 is a divergent member of the Robo family which instead of being a positive regulator of Slit responsiveness, antagonizes Slit responsiveness in precrossing axons. The Slit-Robo interaction is mediated by the second leucine-rich repeat (LRR) domain of Slit and the two N-terminal Ig domains of Robo, Ig1 and Ig2. The primary Robo binding site for Slit2 has been shown by surface plasmon resonance experiments and mutational analysis to be the Ig1 domain, while the Ig2 domain has been proposed to harbor a weak secondary binding site. This group belongs to the I-set of IgSF domains, having A-B-E-D strands in one beta-sheet and A'-G-F-C-C' in the other. Like the V-set Ig domains, members of the I-set have a discontinuous A strand, but lack a C" strand.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 16751923 192 PSPQAVQVGGTASLHCDVSGRPPPAVTWEKQSHQRENLIMRPDQMYGNVVVTSIGQLVLYNARPEDAGLYTCTARNAAGL 271
Cdd:cd05726   6 PRDQVVALGRTVTFQCETKGNPQPAIFWQKEGSQNLLFPYQPPQPSSRFSVSPTGDLTITNVQRSDVGYYICQALNVAGS 85

                ....*....
gi 16751923 272 LRADFPLSV 280
Cdd:cd05726  86 ILAKAQLEV 94

Kunitz domain of papilin, and similar proteins; This model includes the Kunitz domain found in human and mouse papilin, and similar proteins. Papilin is an extracellular matrix glycoprotein that has been found in many organisms to be involved in thin matrix layers during gastrulation, matrix associated with wandering, phagocytic hemocytes, basement membranes and space-filling matrix during Drosophila development. It is a multidomain protein that primarily occurs in basement membranes. Papilins interact with several extracellular matrix components and ADAMTS enzymes, influences cell rearrangements and may modulate metalloproteinases during organogenesis. Papilins exist in mammals and invertebrates as a set of related, though not necessarily identical proteins. Mammalian papilin contains a single Kunitz domain, while other papilins such as that from Caenorhabditis elegans, contains multiple Kunitz domains. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 16751923 359 CVLPAVQG-PCRGWEPRWAYSPLLQQCHPFVYGGCEGNGNNFHSRESCEDAC 409
Cdd:cd22635   1 CLLDKDAGtVCGDYVQRWYYDPATGACNRFWYGGCGGNANRFATEAECLRTC 52

conkunitzin-S1 and -S2, and similar proteins; This model includes Kunitz-type conkunitzin-S1 (Cs1) and -S2 (Cs2). Conkunitzins are pore-modulating toxins that block voltage-dependent potassium channels (Kvs) by exploiting inherent slow inactivation to block K+ channels. Cs1 binds to the channel turrets and disrupts the structural water hydrogen-bonding network, exposing the peripheral water pockets of ion channels and triggering an asymmetric collapse of the pore. Conus bullatus conkunitzin-B1, expressed in the venom duct, specifically blocks voltage-activated potassium channels (Kv) of the Shaker family. Members of this subfamily contain 2 disulfide bonds instead of the 3 present in most Kunitz domain proteins.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 16751923 359 CVLPAVQGpcRGWEP--RWAYSPLLQQCHPFVYGGCEGNGNNFHSRESCEDAC 409
Cdd:cd22593   1 CSLPLDEG--SGNSSltRWYYDPKKGQCKPFTYKGKGGNENNFLTKEDCEETC 51

early lactation protein (ELP), colostrum trypsin inhibitor (CTI), and similar proteins; This model includes the Kunitz-type proteins, colostrum trypsin inhibitor (CTI, also called colostrum BPI) and early lactation protein (ELP). In marsupials, the ELP gene is expressed in the mammary gland and the protein is secreted into milk during early lactation. Mature ELP shares approximately 55.4% similarity with the colostrum-specific bovine CTI protein. Marsupial ELP and eutherian CTI both have a single Kunitz domain and are secreted only during the early lactation phases, suggesting that this protein may have an important role in the immunologically immature young of these species. These proteins are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 16751923 359 CVLPAVQGPCRGWEPRWAYSPLLQQCHPFVYGGCEGNGNNFHSRESCEDAC 409
Cdd:cd22632   4 CQLPPARGPCRSNILRYFYNSTSRECEPFIYGGCNGNANNFETVEMCLRTC 54

Immunoglobulin (Ig)-like ectodomain of the LRIG1 (Leucine-rich Repeats And Immunoglobulin-like Domains Protein 1) and similar proteins; member of the I-set of IgSF domains; The members here are composed of subgroup of the immunoglobulin (Ig) domain found in the Ig superfamily. The Ig superfamily is a heterogenous group of proteins, built on a common fold comprised of a sandwich of two beta sheets. A predominant feature of most Ig domains is a disulfide bridge connecting the two beta-sheets with a tryptophan residue packed against the disulfide bond. The ectodomain of LRIG1 has two distinct regions: the proposed 15 LRRs and three Ig-like domains closer to the membrane. LRIG1 has been reported to interact with many receptor tyrosine kinases, GDNF/c-Ret, E-cadherin, JAK/STAT, c-Met, and the EGFR family signaling systems. Immunoglobulin Superfamily (IgSF) domains can be divided into 4 main classes based on their structures and sequences: the Variable (V), Constant 1 (C1), Constant 2 (C2), and Intermediate (I) sets. The structure of the LRIG1 extracellular Ig domain lacks a C" strand and thus is better described as a member of the I-set of IgSF domains.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 16751923 192 PSPQAVQVGGTASLHCDVSGRPPPAVTWEKQ-------SHQRENLIMRPDQMYgnvvvtsigqlVLYNARPEDAGLYTCT 264
Cdd:cd05763   6 PHDITIRAGSTARLECAATGHPTPQIAWQKDggtdfpaARERRMHVMPEDDVF-----------FIVDVKIEDTGVYSCT 74

                        90
                ....*....|....*..
gi 16751923 265 ARNAAGLLRADFPLSVV 281
Cdd:cd05763  75 AQNSAGSISANATLTVL 91

Drosophila melanogaster Kunitz domains 5, 6, 7, and Caenorhabditis elegans Kunitz domain 5 of papilin, and similar domains; This model includes Kunitz domains from papilins with multiple Kunitz domains, such as Drosophila melanogaster Kunitz domains 5, 6, 7, and Caenorhabditis elegans Kunitz domain 5 of papilin, among others. Papilins are essential for embryonic development. D. melanogaster papilin is an essential extracellular matrix (ECM) protein that influences cell rearrangements. It may act by modulating metalloproteinases action during organogenesis and is able to non-competitively inhibit procollagen N-proteinase, an ADAMTS metalloproteinase. C. elegans papilin (also called abnormal cell migration protein 6) mig-6 encodes long (MIG-6L) and short (MIG-6S) isoforms of the extracellular matrix protein papilin, each required for distinct aspects of distal tip cell (DTC) migration and both isoforms have an N-terminal papilin cassette, lagrin repeats and six C-terminal Kunitz-type serine proteinase inhibitory domains. It plays a role in embryogenesis, the second phase of distal cell tip migration and is required for distribution of the metalloproteinase, mig-17, during organogenesis. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 16751923 359 CVLPAVQGPCRGWEPRWAYSPLLQQCHPFVYGGCEGNGNNFHSRESCEDAC 409
Cdd:cd22637   1 CDQPKDTGPCDNWVLKWYYDSKKGSCRQFYYGGCGGNDNRFDTEEECEARC 51

Drosophila melanogaster Kunitz domain 1, Manduca sexta lacunin Kunitz domain 1, and simialr proteins; This model includes Drosophila melanogaster Kunitz domain 1 of papilin and Manduca sexta Kunitz domain 1 of lacunin, and similar proteins. D. melanogaster papilin is an essential extracellular matrix (ECM) protein that influences cell rearrangements. It may act by modulating metalloproteinase action during organogenesis and is able to non-competitively inhibit procollagen N-proteinase, an ADAMTS metalloproteinase. M. sexta lacunin is a large multidomain ECM containing several domains including several Kunitz-type protease inhibitors, thrombospondin type I, immunoglobulin-like and others. It exerts multiple effects on a variety of cell behaviors associated with the complex phenomenon of epithelial morphogenesis. These domains are similar to Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor) that shows an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 16751923 359 CVLPAVQGPCRGWEPRWAYSPLLQQCHPFVYGGCEGNGNNFHSRESCEDAC 409
Cdd:cd22639   1 CSLPKDRGPCRNYTVKWYFDMAYGGCSRFWYGGCGGNGNRFDTEEECKAVC 51

second Kunitz domain of Carboxypeptidase Inhibitor SmCI and similar domains; This group includes Sabellastarte magnifica carboxypeptidase inhibitor (SmCI), a tri-domain BPTI-Kunitz inhibitor capable of inhibiting serine proteases and A-like metallocarboxypeptidases. While the BPTI-Kunitz family of proteins includes voltage gated channel blockers and inhibitors of serine proteases, SmCI is the only BPTI-Kunitz protein capable of inhibiting metallocarboxypeptidases. Binding studies show that SmCI is able to bind three trypsin molecules under saturating conditions, but only one elastase interacts with the inhibitor. Additionally, SmCI can bind serine proteases and carboxypeptidases at the same time (at least in the ratio 1:1:1), thus becoming the first protease inhibitor that simultaneously blocks these two mechanistic classes of enzymes. This model contains the second Kunitz domain of SmCI, which has a structure similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 16751923 359 CVLPAVQGPCRGWEPRWAYSPLLQQCHPFVYGGCEGNGNNFHSRESCEDAC 409
Cdd:cd22602   1 CSLPSKVGPCRVSARRWFHNPETEKCEVFIYGGCHGNANRFATETECQEVC 51

Kunitz domain found in the amyloid-beta precursor protein (ABPP) subfamily; This subfamily includes the amyloid-beta precursor protein (ABPP, also called APP, APPI, Alzheimer disease amyloid protein, amyloid-beta A4 protein, cerebral vascular amyloid peptide (CVAP), protease nexin II (PN2)), as well as amyloid-like protein 2 (APLP2, also called amyloid protein homolog or APPH), among others. ABPP/APPI is an inhibitor of serine proteases such as anionic and cationic trypsins. For example, APPI-4M is a variant that specifically inhibits Kallikrein (KLK)-related peptidase 6 (KLK6), which is highly upregulated in several types of cancer where its increased activity promotes cancer invasion and metastasis. Amyloid-like protein 2 (APLP2) inhibits trypsin, chymotrypsin, plasmin, factor XIA, and plasma and glandular kallikrein, and may play a role in the regulation of hemostasis. Proteins in this subfamily contain a single Kunitz domain, with a structure similar to those of other Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 16751923 359 CVLPAVQGPCRGWEPRWAYSPLLQQCHPFVYGGCEGNGNNFHSRESCEDAC 409
Cdd:cd22607   2 CSEQAETGPCRAMMPRWYFDVTEGKCAPFIYGGCGGNRNNFESEEYCMAVC 52

Immunoglobulin (Ig)-like domain of myotilin, palladin, and myopalladin; member of the I-set of Ig superfamily (IgSF) domains; The members here are composed of the immunoglobulin (Ig)-like domain in myotilin, palladin, and myopalladin. Myotilin, palladin, and myopalladin function as scaffolds that regulate actin organization. Myotilin and myopalladin are most abundant in skeletal and cardiac muscle; palladin is ubiquitously expressed in the organs of developing vertebrates and plays a key role in cellular morphogenesis. The three family members each interact with specific molecular partners with all three binding to alpha-actinin; In addition, palladin also binds to vasodilator-stimulated phosphoprotein (VASP) and ezrin, myotilin binds to filamin and actin, and myopalladin also binds to nebulin and cardiac ankyrin repeat protein (CARP). This group belongs to the I-set of IgSF domains, having A-B-E-D strands in one beta-sheet and A'-G-F-C-C' in the other. Like the V-set Ig domains, members of the I-set have a discontinuous A strand, but lack a C" strand.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 16751923 186 PALYSSPSPQAVQVGGTASLHCDVSGRPPPAVTWekqshQRENLIMRPDQMYGNVV-VTSIGQLVLYNARPEDAGLYTCT 264
Cdd:cd05744   1 PHFLQAPGDLEVQEGRLCRFDCKVSGLPTPDLFW-----QLNGKPVRPDSAHKMLVrENGRHSLIIEPVTKRDAGIYTCI 75

                ....*.
gi 16751923 265 ARNAAG 270
Cdd:cd05744  76 ARNRAG 81

Second immunoglobulin (Ig)-like domain of a Follistatin-related protein 5, and similar domains; member of the I-set of Ig superfamily (IgSF) domains; The members here are composed of the second immunoglobulin (Ig)-like domain found in human Follistatin-related protein 5 (FSTL5) and a follistatin-like molecule encoded by the CNS-related Mahya gene. Mahya genes have been retained in certain Bilaterian branches during evolution. They are conserved in Hymenoptera and Deuterostomes, but are absent from other metazoan species such as fruit fly and nematode. Mahya proteins are secretory, with a follistatin-like domain (Kazal-type serine/threonine protease inhibitor domain and EF-hand calcium-binding domain), two Ig-like domains, and a novel C-terminal domain. Mahya may be involved in learning and memory and in processing of sensory information in Hymenoptera and vertebrates. Follistatin is a secreted, multidomain protein that binds activins with high affinity and antagonizes their signaling.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 16751923 186 PALYSSPSPQAVQVGGTASLHCDVSGRPPPAVTWEKQshqreNLIMRPDQMYGNVVVTSIGQLVLYNARPEDAGLYTCTA 265
Cdd:cd05736   1 PVIRVYPEFQAKEPGVEASLRCHAEGIPLPRVQWLKN-----GMDINPKLSKQLTLIANGSELHISNVRYEDTGAYTCIA 75

                ....*...
gi 16751923 266 RNAAGLLR 273
Cdd:cd05736  76 KNEGGVDE 83

Fourth Ig-like domain from smooth muscle myosin light chain kinase and similar domains ; a member of the I-set of IgSF domains; The members here are composed of the fourth immunoglobulin (Ig)-like domain from smooth muscle myosin light chain kinase (MYLK) and similar domains. The Ig superfamily (IgSF) is a heterogenous group of proteins, built on a common fold comprised of a sandwich of two beta sheets. IgSF domains can be divided into 4 main classes based on their structures and sequences: the Variable (V), Constant 1 (C1), Constant 2 (C2), and Intermediate (I) sets. Unlike the V-set, one of the distinctive features of I-set domains is the lack of a C" strand. The structure of this group shows that the fourth Ig-like domain from myosin light chain kinase lacks this strand and thus belongs to the I-set of the IgSF. I-set domains are found in several cell adhesion molecules (such as VCAM, ICAM, and MADCAM), and are also present in numerous other diverse protein families, including several tyrosine-protein kinase receptors, the hemolymph protein hemolin, the muscle proteins titin, telokin, and twitchin, the neuronal adhesion molecule axonin-1, and the signaling molecule semaphorin 4D that is involved in axonal guidance, immune function and angiogenesis.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 16751923 185 PPALYSSPSPQAVQVGGTASLHCDVSGRPPPAVTWEKQSHQrenLIMRPDQMYGNVVVtsiGQLVLYNARPEDAGLYTCT 264
Cdd:cd20976   1 APSFSSVPKDLEAVEGQDFVAQCSARGKPVPRITWIRNAQP---LQYAADRSTCEAGV---GELHIQDVLPEDHGTYTCL 74

                        90
                ....*....|....*.
gi 16751923 265 ARNAAGLLRADFPLSV 280
Cdd:cd20976  75 AKNAAGQVSCSAWVTV 90

dendrotoxins I, K, B and similar proteins; This group includes toxins isolated from snake venoms, such as dendrotoxins (DTXs) I, K and B, mambaquaretin-1 (MQ-1) and calcicludine. The dendrotoxins have little or no anti-protease activity but have been shown to block certain subtypes of voltage dependent potassium channels in neurons. Dendroaspis angusticeps (green mamba) alpha-dendrotoxin is a neurotoxin that enhances acetylcholine release at neuromuscular junctions. Studies with cloned K(+) channels show that this toxin blocks Kv1.1, Kv1.2 and Kv1.6 channels in the nanomolar range, whereas Dendroaspis polylepis (black mamba) dendrotoxin K preferentially blocks Kv1.1 channels. Also, structural analogs of dendrotoxins have facilitated defining the molecular recognition properties of different types of K(+) channels, and therefore, dendrotoxins are widely used as probes for studying the function of K(+) channels in physiology and pathophysiology. The structures of these toxins are similar to that of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor), showing an alpha/beta fold with irregular secondary structure stabilized by three disulfide bonds.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 16751923 358 ACVLPAVQGPCRGWEPRWAYSPLLQQCHPFVYGGCEGNGNNFHSRESCEDAC 409
Cdd:cd22595   3 FCKLPVRPGPCKAFISAFYYNWKAKKCHPFTYSGCGGNANRFKTIEECRRTC 54

scorpion venom Kunitz-type toxin (KTT) such as LmKTT-1a, BmKTT-1, and BmKTT-2; This model includes scorpion Kunitz-type toxin (KTT) such as Lychas mucronatus LmKTT-1a (also called Delta-KTx 2.1 or SdPII), Mesobuthus martensii BmKTT-1 (also called Delta-KTx 2.4) and BmKTT-2 (also called Delta-KTx 3.1), all expressed by the venom gland. LmKTT-1a, BmKTT-1 and BmKTT-2 are all dual-function toxins that completely inhibit trypsin activity but have no effect on chymotrypsin or elastase. They also inhibit mKv1.3/KCNA3 potassium channel currents. The structures of these domains are similar to those of Kunitz-type proteinase inhibitors such as BPTI (bovine pancreatic trypsin inhibitor); however, they lack the conserved CysII-CysIV disulfide bond but contains 2 cysteine residues at the C-terminus that generate a new disulfide bond.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|.
gi 16751923 359 CVLPAVQGPCRGWEPRWAYSPLLQQCHPFVYGGCEGNGNNFHSRESCEDAC 409
Cdd:cd22620   3 CQLPSDTGRGKASFTRYYYNEESGKCETFIYGGVGGNSNNFLTKEDCCKEC 53