EF-hand, extracellular calcium-binding (EC) motif, found in secreted protein acidic and rich in cysteine (SPARC)-like proteins; The SPARC protein family represents a diverse group of proteins that share a follistatin-like (FS) domain and an extracellular calcium-binding (EC) domain with two EF-hand motifs. It includes SPARC (for secreted protein acidic and rich in cysteine, also termed osteonectin/ON, or basement-membrane protein 40/BM-40), SPARC-like protein 1 (for secreted protein, acidic and rich in cysteines-like 1/ SPARCL1, also termed high endothelial venule protein/Hevi, or MAST 9, or SC-1, or RAGS-1, or QR1, or ECM 2), testicans 1, 2, and 3 (also termed SPARC/osteonectin, CWCV, and Kazal-like domains proteoglycans, or SPOCK), secreted modular calcium-binding protein SMOC-1 (also termed SPARC-related modular calcium-binding protein 1) and SMOC-2 (also termed SPARC-related modular calcium-binding protein 2, or smooth muscle-associated protein 2/SMAP-2), follistatin-related protein 1 (FRP-1, also termed follistatin-like protein 1/fstl-1, TSC-36/Flik, TGF-beta inducible protein). The SPARC proteins have been implicated in modulating cell interaction with the extracellular milieu, including regulation of extracellular matrix assembly and deposition, counter-adhesion, effects on extracellular protease activity, and modulation of growth factor/cytokine signaling pathways, as well as in development and disease.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1721867783 219 CSDRDLHSLASRLKDWFGVLHLDANRDLKASDSSDSaQGRFDTSILPICKDSLGWMFNKLDLNFDLLLDQSELSTLYLDK 298
Cdd:cd16237     1 CTDKELRNLASRLKDWFGALHEDANRVIKPTSSFTA-QGRFDTSILPICKDSLGWMFNKLDMNYDLLLDPSEISAIYLDK 79

                          90       100       110
                  ....*....|....*....|....*....|...
gi 1721867783 299 YELCMKPLFNSCDSFKDGKLSNNEWCYCFQKPE 331
Cdd:cd16237    80 YEPCMKPLFNSCDSFKDGKLSNNEWCYCFQKPG 112

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

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|..
gi 1721867783  158 CPAIaYGPVCGSDGHIYSSQCKLDFHGCMSGKVLSVKCYGLC 199
Cdd:smart00280   6 CPRE-YDPVCGSDGVTYSNECHLCKAACESGKSIEVKHDGPC 46

EF-hand, extracellular calcium-binding (EC) motif, found in testican-1 (TICN1); TICN1, also termed protein SPOCK, or SPARC/osteonectin, CWCV, and Kazal-like domains proteoglycan 1 (Spock1), is a secreted chimeric proteoglycan that is highly expressed in brain and carries both chondroitin and heparan sulfate glycosaminoglycan side chains. It promotes resistance against Pseudomonas aeruginosa-induced keratitis through regulation of matrix metalloproteinase (MMP)-2 expression and activation. It also acts as a potential cancer prognostic marker that promotes the proliferation and metastasis of gallbladder cancer cells by activating the PI3K/Akt pathway. Moreover, TICN1 corresponding gene SPOCK1 is a novel transforming growth factor-beta target gene that regulates lung cancer cell epithelial-mesenchymal transition. It is also up-regulated by chromodomain helicase/adenosine triphosphatase DNA binding protein 1-like (CHD1L), and promotes human hepatocellular carcinoma (HCC) cell invasiveness and metastasis. Furthermore, TICN1 inhibits the lysosomal cysteine protease cathepsin L in intracellular vesicles and in the extracellular milieu. TICN1 contains an N-terminal signal sequence known to direct nascent polypeptides to the extracellular space, an unique region to the testicans, a follistatin (FS)-like domain generally involving five disulfide bridges, an extracellular calcium-binding (EC) domain including a pair of EF hands, and a thyroglobulin type-1 (TY) domain followed by a C-terminal acidic region with high density of negatively charged amino acids. The substitution of a ligating Asp residue by Phe291 in the +Y position of EF-hand 2 in TICN1 could prevent Ca2+ binding to this site and also cause EF-hand 1 to bind one Ca2+ ion with low affinity.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1721867783 219 CSDRDLHSLASRLKDWFGVLHLDANRDLKASDSSDSaQGRFDTSILPICKDSLGWMFNKLDLNFDLLLDQSELSTLYLDK 298
Cdd:cd16237     1 CTDKELRNLASRLKDWFGALHEDANRVIKPTSSFTA-QGRFDTSILPICKDSLGWMFNKLDMNYDLLLDPSEISAIYLDK 79

                          90       100       110
                  ....*....|....*....|....*....|...
gi 1721867783 299 YELCMKPLFNSCDSFKDGKLSNNEWCYCFQKPE 331
Cdd:cd16237    80 YEPCMKPLFNSCDSFKDGKLSNNEWCYCFQKPG 112

Thyroglobulin type I repeats.; The N-terminal region of human thyroglobulin contains 11 type-1 repeats TY repeats are proposed to be inhibitors of cysteine proteases

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1721867783 334 PCQNEKSKIQLQGRQKSLIGAYIPRCTEVGYFKPTQCHGSTGQCWCVDKYGNEIAGSRKQ-GNPSC 398
Cdd:cd00191     1 PCERERASALESLAGPKLSGLYVPQCDEDGNYEPVQCHGSTGYCWCVDPDGEEIPGTRTRgGPPNC 66

Thyroglobulin type I repeats; The N-terminal region of human thyroglobulin contains 11 type-1 repeats TY repeats are proposed to be inhibitors of cysteine proteases and binding partners of heparin.

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*.
gi 1721867783  356 IPRCTEVGYFKPTQCHGSTGQCWCVDKYGNEIAGSRKQGN-PSCDE 400
Cdd:smart00211   1 IPQCDEDGNYEPVQCDGSSGQCWCVDATGREIPGTRTEGGdPDCPS 46

Kazal-type serine protease inhibitor domain; Usually indicative of serine protease inhibitors. However, kazal-like domains are also seen in the extracellular part of agrins, which are not known to be protease inhibitors. Kazal domains often occur in tandem arrays. Small alpha+beta fold containing three disulphides.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 1721867783 155 CRPCPAIAYGPVCGSDGHIYSSQCKLDFHGCMSGKVLSV-KCYGLCPC 201
Cdd:pfam07648   3 NCQCPKTEYEPVCGSDGVTYPSPCALCAAGCKLGKEVKEeKVKYDGSC 50

EF-hand, extracellular calcium-binding (EC) motif, found in testican-1 (TICN1); TICN1, also termed protein SPOCK, or SPARC/osteonectin, CWCV, and Kazal-like domains proteoglycan 1 (Spock1), is a secreted chimeric proteoglycan that is highly expressed in brain and carries both chondroitin and heparan sulfate glycosaminoglycan side chains. It promotes resistance against Pseudomonas aeruginosa-induced keratitis through regulation of matrix metalloproteinase (MMP)-2 expression and activation. It also acts as a potential cancer prognostic marker that promotes the proliferation and metastasis of gallbladder cancer cells by activating the PI3K/Akt pathway. Moreover, TICN1 corresponding gene SPOCK1 is a novel transforming growth factor-beta target gene that regulates lung cancer cell epithelial-mesenchymal transition. It is also up-regulated by chromodomain helicase/adenosine triphosphatase DNA binding protein 1-like (CHD1L), and promotes human hepatocellular carcinoma (HCC) cell invasiveness and metastasis. Furthermore, TICN1 inhibits the lysosomal cysteine protease cathepsin L in intracellular vesicles and in the extracellular milieu. TICN1 contains an N-terminal signal sequence known to direct nascent polypeptides to the extracellular space, an unique region to the testicans, a follistatin (FS)-like domain generally involving five disulfide bridges, an extracellular calcium-binding (EC) domain including a pair of EF hands, and a thyroglobulin type-1 (TY) domain followed by a C-terminal acidic region with high density of negatively charged amino acids. The substitution of a ligating Asp residue by Phe291 in the +Y position of EF-hand 2 in TICN1 could prevent Ca2+ binding to this site and also cause EF-hand 1 to bind one Ca2+ ion with low affinity.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1721867783 219 CSDRDLHSLASRLKDWFGVLHLDANRDLKASDSSDSaQGRFDTSILPICKDSLGWMFNKLDLNFDLLLDQSELSTLYLDK 298
Cdd:cd16237     1 CTDKELRNLASRLKDWFGALHEDANRVIKPTSSFTA-QGRFDTSILPICKDSLGWMFNKLDMNYDLLLDPSEISAIYLDK 79

                          90       100       110
                  ....*....|....*....|....*....|...
gi 1721867783 299 YELCMKPLFNSCDSFKDGKLSNNEWCYCFQKPE 331
Cdd:cd16237    80 YEPCMKPLFNSCDSFKDGKLSNNEWCYCFQKPG 112

EF-hand, extracellular calcium-binding (EC) motif, found in testicans; Testicans are nervous system-expressed proteoglycans that play important roles in the regulation of protease activity, as well as in the determination of age at menarche. Testican-1 (TICN1, also termed protein SPOCK) is a secreted chimeric proteoglycan that is highly expressed in brain and carries both chondroitin and heparan sulfate glycosaminoglycan side chains. It has been implicated in autoimmune disease. It also acts as a regulator of bone morphogenetic protein (BMP) signaling and show critical functions in the nervous system. Testican-2 (TICN2, also termed protein SPOCK2) is an extracellular heparan sulphate proteoglycan highly expressed in brain. It may play regulatory roles in the development of the central nervous system. It also participates in diverse steps of neurogenesis. TICN1, but not TICN2, inhibits cathepsin L. TICN1 also inhibits attachment and neurite outgrowth in cultures of N2A neuroblastoma cells, While TICN2 is able to inhibit neurite outgrowth from primary cerebellar cells. Testicans contain an N-terminal signal peptide, a testican-specific domain followed by a follistatin-like (FS) domain, an extracellular calcium-binding (EC) domain including a pair of EF hands, a thyroglobulin-like domain (TY), and a C-terminal region with two putative glycosaminoglycan attachment sites. The substitution of a ligating Asp residue by Tyr orTyr in the +Y position of EF hand 2 in testican-2 could prevent Ca2+ binding to this site and also cause EF-hand 1 to bind one Ca2+ with low affinity. The substitution of a ligating Asp residue by Phe or Tyr in the +Y position of EF-hand 2 in testicans could prevent Ca2+ binding to this site and also cause EF-hand 1 to bind one Ca2+ ion with low affinity.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1721867783 219 CSDRDLHSLASRLKDWFGVLHLDANRDLKasdssDSAQGRFDTSILPICKDSLGWMFNKLDLNFDLLLDQSELSTLYLDK 298
Cdd:cd16232     1 CTESELSEMGDRLLDWFSVLHEQSNKAKK-----TSSSKRFDKSHLPECKPSVGWMFNQLDTNNDLHLSQSELYDLELDK 75

                          90       100       110
                  ....*....|....*....|....*....|...
gi 1721867783 299 YELCMKPLFNSCDSFKDGKLSNNEWCYCFQKPE 331
Cdd:cd16232    76 YEPCIKPFLDSCDRNKDGKISSDEWCDCFQRAD 108

Secreted protein acidic and rich in cysteine Ca binding region; The SPARC_Ca_bdg domain of Secreted Protein Acidic and Rich in Cysteine is responsible for the anti-spreading activity of human urothelial cells. It is rich in alpha-helices. This extracellular calcium-binding domain contains two EF-hands that each coordinates one Ca2+ ion, forming a helix-loop-helix structure that not only drives the conformation of the protein but is also necessary for biological activity. The anti-spreading activity was dependent on the coordination of Ca2+ by a Glu residue at the Z position of EF-hand 2.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1721867783 219 CSDRDLHSLASRLKDWFgVLHLDANRDLKASDSSDSAQGRFDTSIL-PICKDSLGWMFNKLDLNFDLLLDQSELSTLY-- 295
Cdd:pfam10591   3 CTDEELAEFPRRMRDWL-KLLLEALRNRRERKDHSSTLEKRDESLLyPCCKDPLGWMFKRLDTNDDLLLDHEELAPIRap 81

                          90       100       110
                  ....*....|....*....|....*....|
gi 1721867783 296 LDKYELCMKPLFNSCDSFKDGKLSNNEWCY 325
Cdd:pfam10591  82 LKPEEHCIKPFFESCDANKDKLISLEEWCC 111

Thyroglobulin type-1 repeat; Thyroglobulin type 1 repeats are thought to be involved in the control of proteolytic degradation. The domain usually contains six conserved cysteines. These form three disulphide bridges. Cysteines 1 pairs with 2, 3 with 4 and 5 with 6.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1721867783 335 CQNEKSKIQLQ-GRQKSLIGAYIPRCTEVGYFKPTQCHGSTGQCWCVDKYGNEIAGSRKQ-GNPSC 398
Cdd:pfam00086   1 CERERARALEQaASGRPASGLYIPNCDEDGFYKPVQCHGSTGYCWCVDPEGQEIPGTRTRgGDPDC 66

EF-hand, extracellular calcium-binding (EC) motif, found in secreted protein acidic and rich in cysteine (SPARC)-like proteins; The SPARC protein family represents a diverse group of proteins that share a follistatin-like (FS) domain and an extracellular calcium-binding (EC) domain with two EF-hand motifs. It includes SPARC (for secreted protein acidic and rich in cysteine, also termed osteonectin/ON, or basement-membrane protein 40/BM-40), SPARC-like protein 1 (for secreted protein, acidic and rich in cysteines-like 1/ SPARCL1, also termed high endothelial venule protein/Hevi, or MAST 9, or SC-1, or RAGS-1, or QR1, or ECM 2), testicans 1, 2, and 3 (also termed SPARC/osteonectin, CWCV, and Kazal-like domains proteoglycans, or SPOCK), secreted modular calcium-binding protein SMOC-1 (also termed SPARC-related modular calcium-binding protein 1) and SMOC-2 (also termed SPARC-related modular calcium-binding protein 2, or smooth muscle-associated protein 2/SMAP-2), follistatin-related protein 1 (FRP-1, also termed follistatin-like protein 1/fstl-1, TSC-36/Flik, TGF-beta inducible protein). The SPARC proteins have been implicated in modulating cell interaction with the extracellular milieu, including regulation of extracellular matrix assembly and deposition, counter-adhesion, effects on extracellular protease activity, and modulation of growth factor/cytokine signaling pathways, as well as in development and disease.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1721867783 219 CSDRDLHSLASRLKDWFGVLH-LDANRDLKASDSSDSAQGRfdtsilpICKDSLGWMFNKLDLNFDLLLDQSELSTL--Y 295
Cdd:cd00252     1 CPGSELMQFPDRLLDWLLLLKeQDENRSYDNNKRGHDLSGT-------MRKEIAQWEFDNLDNNKDGKLDKRELAPFraP 73

                          90       100       110
                  ....*....|....*....|....*....|..
gi 1721867783 296 LDKYELCMKPLFNSCDSFKDGKLSNNEWCYCF 327
Cdd:cd00252    74 LMPLEHCARGFFESCDLNKDKKISLQEWLGCF 105

Kazal-type serine protease inhibitor domain; Usually indicative of serine protease inhibitors. However, kazal-like domains are also seen in the extracellular part of agrins, which are not known to be protease inhibitors. Kazal domains often occur in tandem arrays. Small alpha+beta fold containing three disulphides.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 1721867783 155 CRPCPAIAYGPVCGSDGHIYSSQCKLDFHGCMSGKVLSV-KCYGLCPC 201
Cdd:pfam07648   3 NCQCPKTEYEPVCGSDGVTYPSPCALCAAGCKLGKEVKEeKVKYDGSC 50

Solute carrier organic anion transporters of the Major Facilitator Superfamily of transporters; Solute carrier organic anion transporters (SLCOs) are also called organic anion transporting polypeptides (OATPs) or SLC21 (Solute carrier family 21) proteins. They are sodium-independent transporters that mediate the transport of a broad range of endo- as well as xenobiotics. Their substrates are mainly amphipathic organic anions with a molecular weight of more than 300Da, although there are a few known neutral or positively charged substrates. These include drugs including statins, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, antibiotics, antihistaminics, antihypertensives, and anticancer drugs. SLCOs/OATPs can be classified into 6 families (SLCO1-6 or OATP1-6) and each family may have subfamilies (e.g. OATP1A, OATP1B, OATP1C). Within the subfamilies, individual members are numbered according to the chronology of their identification and if there is already an ortholog known, they are given the same number. For example, the first SLCO identified, is rat OATP1A1 (encoded by the Slco1a1 gene). The second SLCO identified is the first human SLCO from the same subfamily and is called OATP1A2 (encoded by the SLCO1A2 gene). There are 11 human SLCOs/OATPs. SLCOs belong to the Major Facilitator Superfamily (MFS) of membrane transport proteins, which are thought to function through a single substrate binding site, alternating-access mechanism involving a rocker-switch type of movement.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1721867783 158 CPAIAYGPVCGSDGHIYSSQCkldFHGCM-SGKVLSVKCYGLCPCLPGQEASRPARPTTKAVCSD 221
Cdd:cd17336   318 CSDSSFSPVCGSDGITYFSPC---HAGCTsSDAGNGTKTYSNCSCINSGTATSSGCPPDCSVAPN 379

Solute carrier organic anion transporter 4 family of the Major Facilitator Superfamily of transporters; The Solute carrier organic anion transporter 4 (SLCO4) or Organic anion transporting polypeptide 4 (OATP4) family contains two families: OATP4A and OATP4C, each containing one mammalian member, OATP4A1 and OATP4C1, respectively. OATP4A1 (encoded by SLCO4A1), is ubiquitously expressed and mediates the Na(+)-independent transport of the thyroid hormones T3 (triiodo-L-thyronine), T4 (thyroxine) and rT3, and other organic anions such as estrone sulfate and taurocholate. OATP4C1 (encoded by SLCO4C1) is capable of transporting pharmacological substances such as digoxin, ouabain, thyroxine, methotrexate, cAMP, and uremic toxins, which accumulate in patients with chronic kidney diseases (CKDs). The SLCO4/OATP4 family belongs to the Solute carrier organic anion transporter [SLCO, also called organic anion transporting polypeptides (OATPs) or Solute carrier family 21] family of the Major Facilitator Superfamily (MFS) of transporters. MFS proteins are thought to function through a single substrate binding site, alternating-access mechanism involving a rocker-switch type of movement.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1721867783 158 CPAIAYGPVCGSDGHIYSSQCkldFHGCM-SGKVLSVKCYGLCPCLPGQEASRPARPTTKAVCSDRDLHSL 227
Cdd:cd17403   326 CSEDFYDPVCGSDGVTYYSPC---HAGCTtSHGDDGQKVYSNCSCIQSNSSKTSTAATGKACPCETCCQKL 393

EF-hand, extracellular calcium-binding (EC) motif, found in secreted protein acidic and rich in cysteine (SPARC) and similar proteins; This family includes secreted protein acidic and rich in cysteine (SPARC), secreted protein, acidic and rich in cysteine-like 1 (SPARCL1), and similar proteins. SPARC is a prototypic collagen-binding matricellular protein that is involved in extracellular matrix (ECM) assembly and fibrosis through binding both fibrillar collagen and basal lamina collagen IV. It regulates the activity of matrix metalloproteinases (MMPs), as well as the growth factor signaling mediated by cell surface receptors including vascular endothelial growth factor (VEGF) receptor, basic fibroblast growth factor (bFGF), and transforming growth factor (TGF) beta1. It also shows survival activity in tumor progression. SPARC contains an N-terminal acidic 52-residue segment followed by a follistatin-like (FS) domain, and an alpha-helical EC domain with 2 unusual calcium-binding EF-hands and the collagen-binding site. SPARCL1 is the closest family member to SPARC. It shares the three primary domains contained within SPARC with an expanded N-terminal domain. SPARCL1 may function as both a tumor suppressor and as a regulator of angiogenesis. It can bind to collagens and be counter-adhesive to wild-type dermal fibroblasts, but do not influence rates of cell proliferation. Moreover, SPARCL1 can influence central nervous system (CNS) development and synaptic rearrangement.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1721867783 219 CSDRDLHSLASRLKDW-FGVLHLDANRD----LKASDSSDSAQGRFDTSILPICkdslgWMFNK-LDLNFDLLLDQSELS 292
Cdd:cd16231     1 CLDEELSEFPLRMRDWlKNVMVQLAERDelheGLTEKELEDFQKNYKMYVYPVH-----WKFCDlDQHPHDRYLSHHELA 75

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|.
gi 1721867783 293 TLY--LDKYELCMKPLFNSCDSFKDGKLSNNEWCYCFQKPE 331
Cdd:cd16231    76 PLRapLVPMEHCTTPFLETCDADNDKLISLKEWGACLGLKE 116