EF-hand, extracellular calcium-binding (EC) motif, found in secreted modular calcium-binding protein 1 (SMOC-1); SMOC-1, also termed SPARC-related modular calcium-binding protein 1, or smooth muscle-associated protein 1 (SMAP-1), is an Arf6 GTPase-activating protein (GAP) that directly interacts with clathrin and regulates the clathrin-dependent endocytosis of transferrin receptors from the plasma membrane. It is predominantly localized in basement membranes. SMOC-1 acts as a regulator of osteoblast differentiation and is involved in inhibition of transforming growth factor-beta (TGF-beta) signaling through production of nitric oxide. It also plays an essential role in ocular and limb development and functions as a regulator of bone morphogenic protein (BMP) signaling. It interacts with a matricellular protein, tenascin C in addition to the serum proteins, fibulin-1 and C-reactive protein, but not collagens. Two point mutations in the SMOC1 gene may cause Waardenburg Anophtalmia Syndrome. Moreover, SMOC-1 is involved in direct or indirect modulation of growth factor signaling pathways and plays a role in physiological processes involving extensive tissue remodeling. SMOC-1 contains a follistatin-like (FS) domain, two thyroglobulin-like (TY) domains, a novel domain, which is found only in the homologous SMOC-2, and an extracellular calcium-binding (EC) domain with two EF-hand calcium-binding motifs.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 38258649 315 CPEGKKMEFITSLLDALTTDMVQAINSAAPTGGGRFSEPDPSHTLEERVVHWYFSQLDSNSSNDINKREMKPFKRYVKKK 394
Cdd:cd16240   1 CPEGKKLEFITSLLDALTTDMVQAINSAAPTGGGRFSEPDPSHTLEERVVHWYFSQLDNNSSNDINKKELKPFKRYVKKK 80

                        90       100       110
                ....*....|....*....|....*....|....*
gi 38258649 395 AKPKKCARRFTDYCDLNKDKVISLPELKGCLGVSK 429
Cdd:cd16240  81 AKPKKCARRFTDYCDLNKDKSISLQELKGCLGVSK 115

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 38258649   227 CDQERQSALEEAQ-QNPREGIVIPECAPGGLYKPVQCHQSTGYCWCVLVDtGRPLPGTSTRYVMPSC 292
Cdd:pfam00086   1 CERERARALEQAAsGRPASGLYIPNCDEDGFYKPVQCHGSTGYCWCVDPE-GQEIPGTRTRGGDPDC 66

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 38258649  47 CSRtQPKPICASDGRSYESMCEYQRAKCR-DPTLGVVHRGRC 87
Cdd:cd00104   1 CPK-EYDPVCGSDGKTYSNECHLGCAACRsGRSITVAHNGPC 41

EF-hand, extracellular calcium-binding (EC) motif, found in secreted modular calcium-binding protein 1 (SMOC-1); SMOC-1, also termed SPARC-related modular calcium-binding protein 1, or smooth muscle-associated protein 1 (SMAP-1), is an Arf6 GTPase-activating protein (GAP) that directly interacts with clathrin and regulates the clathrin-dependent endocytosis of transferrin receptors from the plasma membrane. It is predominantly localized in basement membranes. SMOC-1 acts as a regulator of osteoblast differentiation and is involved in inhibition of transforming growth factor-beta (TGF-beta) signaling through production of nitric oxide. It also plays an essential role in ocular and limb development and functions as a regulator of bone morphogenic protein (BMP) signaling. It interacts with a matricellular protein, tenascin C in addition to the serum proteins, fibulin-1 and C-reactive protein, but not collagens. Two point mutations in the SMOC1 gene may cause Waardenburg Anophtalmia Syndrome. Moreover, SMOC-1 is involved in direct or indirect modulation of growth factor signaling pathways and plays a role in physiological processes involving extensive tissue remodeling. SMOC-1 contains a follistatin-like (FS) domain, two thyroglobulin-like (TY) domains, a novel domain, which is found only in the homologous SMOC-2, and an extracellular calcium-binding (EC) domain with two EF-hand calcium-binding motifs.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 38258649 315 CPEGKKMEFITSLLDALTTDMVQAINSAAPTGGGRFSEPDPSHTLEERVVHWYFSQLDSNSSNDINKREMKPFKRYVKKK 394
Cdd:cd16240   1 CPEGKKLEFITSLLDALTTDMVQAINSAAPTGGGRFSEPDPSHTLEERVVHWYFSQLDNNSSNDINKKELKPFKRYVKKK 80

                        90       100       110
                ....*....|....*....|....*....|....*
gi 38258649 395 AKPKKCARRFTDYCDLNKDKVISLPELKGCLGVSK 429
Cdd:cd16240  81 AKPKKCARRFTDYCDLNKDKSISLQELKGCLGVSK 115

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 38258649   227 CDQERQSALEEAQ-QNPREGIVIPECAPGGLYKPVQCHQSTGYCWCVLVDtGRPLPGTSTRYVMPSC 292
Cdd:pfam00086   1 CERERARALEQAAsGRPASGLYIPNCDEDGFYKPVQCHGSTGYCWCVDPE-GQEIPGTRTRGGDPDC 66

Thyroglobulin_1 repeat associated disordered domain; This domain of conserved disorder lies almost invariably between the two repeated Thyroglobulin_1 domains, pfam00086.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 38258649   159 SGSVTDKPLSQGNSGRkdDGSKPTPTMETQPVFDGDEITA--PTLWIKHLVIKDSKLNNTNIR 219
Cdd:pfam16597   1 SGSVTEKPPQREGSGK--DGSKPTPTMETQPVFDEEDITSqyPTLWTEQVVSRQNKRNKANSS 61

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 38258649    248 IPECAPGGLYKPVQCHQSTGYCWCVLvDTGRPLPGTSTRYVMPSCES 294
Cdd:smart00211   1 IPQCDEDGNYEPVQCDGSSGQCWCVD-ATGREIPGTRTEGGDPDCPS 46

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 38258649  47 CSRtQPKPICASDGRSYESMCEYQRAKCR-DPTLGVVHRGRC 87
Cdd:cd00104   1 CPK-EYDPVCGSDGKTYSNECHLGCAACRsGRSITVAHNGPC 41

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        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 38258649    42 QCNLHCSRTQPKPICASDGRSYESMCEYQRAKCR----DPTLGVVHRGRC 87
Cdd:pfam07648   1 NCNCQCPKTEYEPVCGSDGVTYPSPCALCAAGCKlgkeVKEEKVKYDGSC 50

EF-hand, extracellular calcium-binding (EC) motif, found in secreted modular calcium-binding protein 1 (SMOC-1); SMOC-1, also termed SPARC-related modular calcium-binding protein 1, or smooth muscle-associated protein 1 (SMAP-1), is an Arf6 GTPase-activating protein (GAP) that directly interacts with clathrin and regulates the clathrin-dependent endocytosis of transferrin receptors from the plasma membrane. It is predominantly localized in basement membranes. SMOC-1 acts as a regulator of osteoblast differentiation and is involved in inhibition of transforming growth factor-beta (TGF-beta) signaling through production of nitric oxide. It also plays an essential role in ocular and limb development and functions as a regulator of bone morphogenic protein (BMP) signaling. It interacts with a matricellular protein, tenascin C in addition to the serum proteins, fibulin-1 and C-reactive protein, but not collagens. Two point mutations in the SMOC1 gene may cause Waardenburg Anophtalmia Syndrome. Moreover, SMOC-1 is involved in direct or indirect modulation of growth factor signaling pathways and plays a role in physiological processes involving extensive tissue remodeling. SMOC-1 contains a follistatin-like (FS) domain, two thyroglobulin-like (TY) domains, a novel domain, which is found only in the homologous SMOC-2, and an extracellular calcium-binding (EC) domain with two EF-hand calcium-binding motifs.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 38258649 315 CPEGKKMEFITSLLDALTTDMVQAINSAAPTGGGRFSEPDPSHTLEERVVHWYFSQLDSNSSNDINKREMKPFKRYVKKK 394
Cdd:cd16240   1 CPEGKKLEFITSLLDALTTDMVQAINSAAPTGGGRFSEPDPSHTLEERVVHWYFSQLDNNSSNDINKKELKPFKRYVKKK 80

                        90       100       110
                ....*....|....*....|....*....|....*
gi 38258649 395 AKPKKCARRFTDYCDLNKDKVISLPELKGCLGVSK 429
Cdd:cd16240  81 AKPKKCARRFTDYCDLNKDKSISLQELKGCLGVSK 115

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 38258649 315 CPEGKKMEFITSLLDALTTDMVQAINSAAPTgggrfsepdPSHTLEERVVHWYFSQLDSNSSNDINKREMKPFKRYVKKK 394
Cdd:cd16234   1 CPEAKKTEFLNNLIDALKTEMVRSGNSNSSA---------PDKSSEEQVLDWKFSQLDKNKNGVLERKEWKPFKRLLKKA 71

                        90       100       110
                ....*....|....*....|....*....|...
gi 38258649 395 AKPKKCARRFTDYCDLNKDKVISLPELKGCLGV 427
Cdd:cd16234  72 VKPKKCARKFPKYCDVNKDKKISLTEWLNCLGV 104

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 38258649    95 CRLERAQALEQAK--KPQEAVFVPECGEDGSFTQVQCHTYTGYCWCVTPDGKPISGSSVQNKTPVC 158
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 38258649  94 KCRLERAQALEQ-AKKPQEAVFVPECGEDGSFTQVQCHTYTGYCWCVTPDGKPISGSSVQNKTPVC 158
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

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 38258649 226 SCDQERQSALEEAQQNPREGIVIPECAPGGLYKPVQCHQSTGYCWCVLVDtGRPLPGTSTRYVMPSC 292
Cdd:cd00191   1 PCERERASALESLAGPKLSGLYVPQCDEDGNYEPVQCHGSTGYCWCVDPD-GEEIPGTRTRGGPPNC 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 38258649    115 VPECGEDGSFTQVQCHTYTGYCWCVTPDGKPISGSSVQNKTPVCS 159
Cdd:smart00211   1 IPQCDEDGNYEPVQCDGSSGQCWCVDATGREIPGTRTEGGDPDCP 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 38258649  47 CSRtQPKPICASDGRSYESMCEYQRAKCR-DPTLGVVHRGRC 87
Cdd:cd00104   1 CPK-EYDPVCGSDGKTYSNECHLGCAACRsGRSITVAHNGPC 41

EF-hand, extracellular calcium-binding (EC) motif, found in secreted protein, acidic and rich in cysteine-like 1 (SPARCL1); SPARCL1, also termed SPARC-like protein 1, or high endothelial venule protein (Hevin), or MAST 9, or SC-1, or RAGS-1, or QR1, or ECM 2, is a diversely expressed and developmentally regulated extracellular matrix glycoprotein involved in tissue repair and remodeling via interaction with the surrounding extracellular matrix (ECM) proteins. It plays a pivotal role in the corneal wound healing. SPARCL1 may function as both a tumor suppressor and as a regulator of angiogenesis. It regulates cell migration/invasion and suppresses metastasis in many cancers, including prostate cancer, colorectal cancer, gastric cancer, and breast cancer. It can bind to collagens and be counter-adhesive to wild-type dermal fibroblasts, but do not influence rates of cell proliferation. Moreover, SPARCL1 contributes to neural development and participates in remodeling events associated with neuronal degeneration following neural injury. It can influence central nervous system (CNS) development and synaptic rearrangement. SPARCL1 is the closest family member to secreted protein acidic and rich in cysteine (SPARC), but does not compensate for the absence of SPARC in the CNS. 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 shares the three primary domains contained within SPARC with an expanded N-terminal domain.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 38258649 364 VHWYFSQLDSNSSND-INKREMKPFKryvKKKAKPKKCARRFTDYCDLNKDKVISLPELKGCLGVSK 429
Cdd:cd16236  30 VHWQFAQLDQHPSDRfLTHSELAPLR---ASLVPMEHCITRFFQECDADKDKLITLKEWCHCFGIKE 93

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        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 38258649    42 QCNLHCSRTQPKPICASDGRSYESMCEYQRAKCR----DPTLGVVHRGRC 87
Cdd:pfam07648   1 NCNCQCPKTEYEPVCGSDGVTYPSPCALCAAGCKlgkeVKEEKVKYDGSC 50

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 38258649   349 RFSEPDPSHTLEER-----------VVHWYFSQLDSNSSNDINKREMKPfkrYVKKKAKPKKCARRFTDYCDLNKDKVIS 417
Cdd:pfam10591  29 RRERKDHSSTLEKRdesllypcckdPLGWMFKRLDTNDDLLLDHEELAP---IRAPLKPEEHCIKPFFESCDANKDKLIS 105

                  ...
gi 38258649   418 LPE 420
Cdd:pfam10591 106 LEE 108