EF-hand, extracellular calcium-binding (EC) motif, found in secreted modular calcium-binding protein 2 (SMOC-2); SMOC-2, also termed SPARC-related modular calcium-binding protein 2, or smooth muscle-associated protein 2 (SMAP-2), is a ubiquitously expressed matricellular protein that enhances the response to angiogenic growth factors, mediate cell adhesion, keratinocyte migration, and metastasis. It is also associated with vitiligo and craniofacial and dental defects. Moreover, SMOC-2 acts as an Arf1 GTPase-activating protein (GAP) that interacts with clathrin heavy chain (CHC) and clathrin assembly protein CALM and functions in the retrograde, early endosome/trans-Golgi network (TGN) pathway in a clathrin- and AP-1-dependent manner. It also contributes to mitogenesis via activation of integrin-linked kinase (ILK). SMOC-2 contains a follistatin-like (FS) domain, two thyroglobulin-like (TY) domains, a novel domain, which is found only in the homologous SMOC-1, and an extracellular calcium-binding (EC) domain with two EF-hand calcium-binding motifs.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 569001325 315 CPGAKKHEFLTSVLDALSTDMVHAVSDPSSSSGRLSEPDPSHTLEERVVHWYFKLLDKNSSGDIGKKEIKPFKRFLRKKS 394
Cdd:cd16241    1 CPGAKKTEFLTSVLDALSTDMVHAVSDPSASSRRLSEPDPSHTLEERVVHWYFKQLDKNSSGDIGKKEIKPFKRFLRKKS 80

                         90       100       110
                 ....*....|....*....|....*....|....
gi 569001325 395 KPKKCVKKFVEYCDMNNDKSITVQELMGCLGVTR 428
Cdd:cd16241   81 KPKKCVKKFVEYCDVNNDKSLSVQELMGCLGVTK 114

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 569001325   90 CVAERKYTQEQAR--KEFQQVFIPECNDDGTYSQVQCHSYTGYCWCVTPNGRPISGTAVAHKTPRC 153
Cdd:pfam00086   1 CERERARALEQAAsgRPASGLYIPNCDEDGFYKPVQCHGSTGYCWCVDPEGQEIPGTRTRGGDPDC 66

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

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*..
gi 569001325    39 DCSLDCPSSPqKPLCASDGRTFLSRCEFQRAKCK-DPQLEIAHRGNC 84
Cdd:smart00280   1 DCPEACPREY-DPVCGSDGVTYSNECHLCKAACEsGKSIEVKHDGPC 46

EF-hand, extracellular calcium-binding (EC) motif, found in secreted modular calcium-binding protein 2 (SMOC-2); SMOC-2, also termed SPARC-related modular calcium-binding protein 2, or smooth muscle-associated protein 2 (SMAP-2), is a ubiquitously expressed matricellular protein that enhances the response to angiogenic growth factors, mediate cell adhesion, keratinocyte migration, and metastasis. It is also associated with vitiligo and craniofacial and dental defects. Moreover, SMOC-2 acts as an Arf1 GTPase-activating protein (GAP) that interacts with clathrin heavy chain (CHC) and clathrin assembly protein CALM and functions in the retrograde, early endosome/trans-Golgi network (TGN) pathway in a clathrin- and AP-1-dependent manner. It also contributes to mitogenesis via activation of integrin-linked kinase (ILK). SMOC-2 contains a follistatin-like (FS) domain, two thyroglobulin-like (TY) domains, a novel domain, which is found only in the homologous SMOC-1, and an extracellular calcium-binding (EC) domain with two EF-hand calcium-binding motifs.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 569001325 315 CPGAKKHEFLTSVLDALSTDMVHAVSDPSSSSGRLSEPDPSHTLEERVVHWYFKLLDKNSSGDIGKKEIKPFKRFLRKKS 394
Cdd:cd16241    1 CPGAKKTEFLTSVLDALSTDMVHAVSDPSASSRRLSEPDPSHTLEERVVHWYFKQLDKNSSGDIGKKEIKPFKRFLRKKS 80

                         90       100       110
                 ....*....|....*....|....*....|....
gi 569001325 395 KPKKCVKKFVEYCDMNNDKSITVQELMGCLGVTR 428
Cdd:cd16241   81 KPKKCVKKFVEYCDVNNDKSLSVQELMGCLGVTK 114

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 569001325   90 CVAERKYTQEQAR--KEFQQVFIPECNDDGTYSQVQCHSYTGYCWCVTPNGRPISGTAVAHKTPRC 153
Cdd:pfam00086   1 CERERARALEQAAsgRPASGLYIPNCDEDGFYKPVQCHGSTGYCWCVDPEGQEIPGTRTRGGDPDC 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

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 569001325  90 CVAERKYTQEQ-ARKEFQQVFIPECNDDGTYSQVQCHSYTGYCWCVTPNGRPISGTAVAHKTPRC 153
Cdd:cd00191    2 CERERASALESlAGPKLSGLYVPQCDEDGNYEPVQCHGSTGYCWCVDPDGEEIPGTRTRGGPPNC 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 569001325   110 IPECNDDGTYSQVQCHSYTGYCWCVTPNGRPISGTAVAHKTPRCP 154
Cdd:smart00211   1 IPQCDEDGNYEPVQCDGSSGQCWCVDATGREIPGTRTEGGDPDCP 45

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

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*..
gi 569001325    39 DCSLDCPSSPqKPLCASDGRTFLSRCEFQRAKCK-DPQLEIAHRGNC 84
Cdd:smart00280   1 DCPEACPREY-DPVCGSDGVTYSNECHLCKAACEsGKSIEVKHDGPC 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
                  ....*....|....*....|....*....|....
gi 569001325   39 DCSLDCPSSPQKPLCASDGRTFLSRCEFQRAKCK 72
Cdd:pfam07648   1 NCNCQCPKTEYEPVCGSDGVTYPSPCALCAAGCK 34

EF-hand, extracellular calcium-binding (EC) motif, found in secreted modular calcium-binding protein 2 (SMOC-2); SMOC-2, also termed SPARC-related modular calcium-binding protein 2, or smooth muscle-associated protein 2 (SMAP-2), is a ubiquitously expressed matricellular protein that enhances the response to angiogenic growth factors, mediate cell adhesion, keratinocyte migration, and metastasis. It is also associated with vitiligo and craniofacial and dental defects. Moreover, SMOC-2 acts as an Arf1 GTPase-activating protein (GAP) that interacts with clathrin heavy chain (CHC) and clathrin assembly protein CALM and functions in the retrograde, early endosome/trans-Golgi network (TGN) pathway in a clathrin- and AP-1-dependent manner. It also contributes to mitogenesis via activation of integrin-linked kinase (ILK). SMOC-2 contains a follistatin-like (FS) domain, two thyroglobulin-like (TY) domains, a novel domain, which is found only in the homologous SMOC-1, and an extracellular calcium-binding (EC) domain with two EF-hand calcium-binding motifs.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 569001325 315 CPGAKKHEFLTSVLDALSTDMVHAVSDPSSSSGRLSEPDPSHTLEERVVHWYFKLLDKNSSGDIGKKEIKPFKRFLRKKS 394
Cdd:cd16241    1 CPGAKKTEFLTSVLDALSTDMVHAVSDPSASSRRLSEPDPSHTLEERVVHWYFKQLDKNSSGDIGKKEIKPFKRFLRKKS 80

                         90       100       110
                 ....*....|....*....|....*....|....
gi 569001325 395 KPKKCVKKFVEYCDMNNDKSITVQELMGCLGVTR 428
Cdd:cd16241   81 KPKKCVKKFVEYCDVNNDKSLSVQELMGCLGVTK 114

EF-hand, extracellular calcium-binding (EC) motif, found in secreted modular calcium-binding protein SMOC-1, SMOC-2, and similar proteins; SMOC proteins corresponds to a group matricellular proteins that are involved in direct or indirect modulation of growth factor signaling pathways and play diverse roles in physiological processes involving extensive tissue remodeling, migration, proliferation, and angiogenesis. They may mediate intercellular signaling and cell type-specific differentiation during gonad and reproductive tract development. SMOC-1 is localized in basement membranes. Its mutations have been found to be associated with individuals with Warrdenburg Anopthalmia Syndrome. SMOC-2 is ubiquitously expressed and is involved in angiogenesis and the regulation of cell cycle progression. It enhances the angiogenic effect of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF). It has also been implicated in generalized vitiligo. SMOC proteins consist of a follistatin-like (FS) domain, two thyroglobulin-like (TY) domains, a novel domain conserved only in SMOC proteins, and an extracellular calcium-binding (EC) domain with two EF-hand calcium-binding motifs.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 569001325 315 CPGAKKHEFLTSVLDALSTDMVHAVSDPSSSsgrlsepdPSHTLEERVVHWYFKLLDKNSSGDIGKKEIKPFKRFLRKKS 394
Cdd:cd16234    1 CPEAKKTEFLNNLIDALKTEMVRSGNSNSSA--------PDKSSEEQVLDWKFSQLDKNKNGVLERKEWKPFKRLLKKAV 72

                         90       100       110
                 ....*....|....*....|....*....|..
gi 569001325 395 KPKKCVKKFVEYCDMNNDKSITVQELMGCLGV 426
Cdd:cd16234   73 KPKKCARKFPKYCDVNKDKKISLTEWLNCLGV 104

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 569001325 315 CPGAKKHEFLTSVLDALSTDMVHAVsDPSSSSGRlSEPDPSHTLEERVVHWYFKLLDKNSSGDIGKKEIKPFKRFLrkkS 394
Cdd:cd00252    1 CPGSELMQFPDRLLDWLLLLKEQDE-NRSYDNNK-RGHDLSGTMRKEIAQWEFDNLDNNKDGKLDKRELAPFRAPL---M 75

                         90       100       110
                 ....*....|....*....|....*....|..
gi 569001325 395 KPKKCVKKFVEYCDMNNDKSITVQELMGCLGV 426
Cdd:cd00252   76 PLEHCARGFFESCDLNKDKKISLQEWLGCFGV 107

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 569001325 226 SCDQEHQSALEEAKQPKNDNVVIPECAHGGLYKPVQCHPSTGYCWCVLVDtGRPIPGTSTRYEQPKC 292
Cdd:cd00191    1 PCERERASALESLAGPKLSGLYVPQCDEDGNYEPVQCHGSTGYCWCVDPD-GEEIPGTRTRGGPPNC 66

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 569001325  227 CDQEHQSALEEAKQPK-NDNVVIPECAHGGLYKPVQCHPSTGYCWCVLVDtGRPIPGTSTRYEQPKC 292
Cdd:pfam00086   1 CERERARALEQAASGRpASGLYIPNCDEDGFYKPVQCHGSTGYCWCVDPE-GQEIPGTRTRGGDPDC 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 569001325   248 IPECAHGGLYKPVQCHPSTGYCWCVLvDTGRPIPGTSTRYEQPKCD 293
Cdd:smart00211   1 IPQCDEDGNYEPVQCDGSSGQCWCVD-ATGREIPGTRTEGGDPDCP 45

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        40
                 ....*....|....*....|....*....|....*....|..
gi 569001325  44 CPSSpQKPLCASDGRTFLSRCEFQRAKCK-DPQLEIAHRGNC 84
Cdd:cd00104    1 CPKE-YDPVCGSDGKTYSNECHLGCAACRsGRSITVAHNGPC 41

EF-hand, extracellular calcium-binding (EC) motif, found in secreted protein acidic and rich in cysteine (SPARC); SPARC, also termed basement-membrane protein 40 (BM-40), or osteonectin (ON), is a prototypic collagen-binding matricellular protein that is essential for embryo development in invertebrates and highly expressed in bone. It participates in normal tissue remodeling as it regulates the deposition of extracellular matrix, as well as in neoplastic transformation. It 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. SPARC shows survival activity in tumor progression. It plays a role in metastatic process to the lung during melanoma progression. It can suppress prostate cancer cell growth and survival. Moreover, SPARC is a bone- associated protein that has a major role in bone development and mineralisationis. It is involved in the initiation and progression of vascular calcification and upregulated by adiponectin. Furthermore, SPARC may be one of the molecules that govern the uptake and delivery of proteins from blood to the cerebrospinal fluid (CSF) during brain development. 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. Platelet-derived growth factor (PDGF) also interacts with its EC domain, but in a calcium-independent manner, whereas collagen binding is calcium-dependent.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 569001325 357 TLEER----VVHWYFKLLDKNS-SGDIGKKEIKPFKRFLrkkSKPKKCVKKFVEYCDMNNDKSITVQELMGCLGV 426
Cdd:cd16235   23 TLYERdyifPVHWQFGQLDQHPiDGYLSHTELAPLRAPL---IPMEHCTTRFFETCDLDNDKYIALDEWAGCFGI 94