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 1864403579 372 CPEGKKMEFITSLLDALTTDMVQAINSAAPTGGGRFSEPDPSHTLEERVVHWYFGQLDSNSSNDINKREMKPFKRYVKKK 451
Cdd:cd16240     1 CPEGKKLEFITSLLDALTTDMVQAINSAAPTGGGRFSEPDPSHTLEERVVHWYFSQLDNNSSNDINKKELKPFKRYVKKK 80

                          90       100       110
                  ....*....|....*....|....*....|....*
gi 1864403579 452 AKPKKCARRFTDYCDLNKDKVISLPELKGCLGVSK 486
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 1864403579 284 CDQERQSALEEA-RQNPREGIVIPECAPGGLYKPVQCHQSTGYCWCVLVDtGRPLPGTSTRYVMPSC 349
Cdd:pfam00086   1 CERERARALEQAaSGRPASGLYIPNCDEDGFYKPVQCHGSTGYCWCVDPE-GQEIPGTRTRGGDPDC 66

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

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*..
gi 1864403579   99 QCNLHCSRTqPKPICASDGRSYESMCEYQRAKC-RDPTLSVVHRGKC 144
Cdd:smart00280   1 DCPEACPRE-YDPVCGSDGVTYSNECHLCKAACeSGKSIEVKHDGPC 46

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 1864403579 372 CPEGKKMEFITSLLDALTTDMVQAINSAAPTGGGRFSEPDPSHTLEERVVHWYFGQLDSNSSNDINKREMKPFKRYVKKK 451
Cdd:cd16240     1 CPEGKKLEFITSLLDALTTDMVQAINSAAPTGGGRFSEPDPSHTLEERVVHWYFSQLDNNSSNDINKKELKPFKRYVKKK 80

                          90       100       110
                  ....*....|....*....|....*....|....*
gi 1864403579 452 AKPKKCARRFTDYCDLNKDKVISLPELKGCLGVSK 486
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 1864403579 284 CDQERQSALEEA-RQNPREGIVIPECAPGGLYKPVQCHQSTGYCWCVLVDtGRPLPGTSTRYVMPSC 349
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

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1864403579 283 SCDQERQSALEEARQNPREGIVIPECAPGGLYKPVQCHQSTGYCWCVLVDtGRPLPGTSTRYVMPSC 349
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 1864403579  305 IPECAPGGLYKPVQCHQSTGYCWCVLvDTGRPLPGTSTRYVMPSCES 351
Cdd:smart00211   1 IPQCDEDGNYEPVQCDGSSGQCWCVD-ATGREIPGTRTEGGDPDCPS 46

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

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*..
gi 1864403579   99 QCNLHCSRTqPKPICASDGRSYESMCEYQRAKC-RDPTLSVVHRGKC 144
Cdd:smart00280   1 DCPEACPRE-YDPVCGSDGVTYSNECHLCKAACeSGKSIEVKHDGPC 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        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 1864403579  99 QCNLHCSRTQPKPICASDGRSYESMCEYQRAKCR----DPTLSVVHRGKC 144
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 1864403579 372 CPEGKKMEFITSLLDALTTDMVQAINSAAPTGGGRFSEPDPSHTLEERVVHWYFGQLDSNSSNDINKREMKPFKRYVKKK 451
Cdd:cd16240     1 CPEGKKLEFITSLLDALTTDMVQAINSAAPTGGGRFSEPDPSHTLEERVVHWYFSQLDNNSSNDINKKELKPFKRYVKKK 80

                          90       100       110
                  ....*....|....*....|....*....|....*
gi 1864403579 452 AKPKKCARRFTDYCDLNKDKVISLPELKGCLGVSK 486
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 1864403579 372 CPEGKKMEFITSLLDALTTDMVQAINSAAPTgggrfsepdPSHTLEERVVHWYFGQLDSNSSNDINKREMKPFKRYVKKK 451
Cdd:cd16234     1 CPEAKKTEFLNNLIDALKTEMVRSGNSNSSA---------PDKSSEEQVLDWKFSQLDKNKNGVLERKEWKPFKRLLKKA 71

                          90       100       110
                  ....*....|....*....|....*....|...
gi 1864403579 452 AKPKKCARRFTDYCDLNKDKVISLPELKGCLGV 484
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 1864403579 152 CRQERTQALEESK--RPQEAVFVPECSEDGSFTQVQCHTYTGYCWCVTPDGKPISGSSVQNKTPIC 215
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 1864403579 151 KCRQERTQALEESKRP-QEAVFVPECSEDGSFTQVQCHTYTGYCWCVTPDGKPISGSSVQNKTPIC 215
Cdd:cd00191     1 PCERERASALESLAGPkLSGLYVPQCDEDGNYEPVQCHGSTGYCWCVDPDGEEIPGTRTRGGPPNC 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 1864403579 216 SGSVTDKPSSQGNSGRkdDGSKPTPTMETQPVFDGDEITA--PTLWIKHLVIKDSKLNNTNIR 276
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 1864403579  172 VPECSEDGSFTQVQCHTYTGYCWCVTPDGKPISGSSVQNKTPICS 216
Cdd:smart00211   1 IPQCDEDGNYEPVQCDGSSGQCWCVDATGREIPGTRTEGGDPDCP 45

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 1864403579 415 TLEER----VVHWYFGQLDSNSSND-INKREMKPFKryvKKKAKPKKCARRFTDYCDLNKDKVISLPELKGCLGVSK 486
Cdd:cd16235    23 TLYERdyifPVHWQFGQLDQHPIDGyLSHTELAPLR---APLIPMEHCTTRFFETCDLDNDKYIALDEWAGCFGIKQ 96

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 1864403579 104 CSRtQPKPICASDGRSYESMCEYQRAKCR-DPTLSVVHRGKC 144
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 1864403579  99 QCNLHCSRTQPKPICASDGRSYESMCEYQRAKCR----DPTLSVVHRGKC 144
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 1864403579 406 RFSEPDPSHTLEER-----------VVHWYFGQLDSNSSNDINKREMKPfkrYVKKKAKPKKCARRFTDYCDLNKDKVIS 474
Cdd:pfam10591  29 RRERKDHSSTLEKRdesllypcckdPLGWMFKRLDTNDDLLLDHEELAP---IRAPLKPEEHCIKPFFESCDANKDKLIS 105

                  ...
gi 1864403579 475 LPE 477
Cdd:pfam10591 106 LEE 108