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 568955021  330 CHTELSNIQKR-QGIKKLLGQYIPLCDEDGYYKPTQCHGSVGQCWCVDRYGNEVVGSR-INGVADC 393
Cdd:pfam00086   1 CERERARALEQaASGRPASGLYIPNCDEDGFYKPVQCHGSTGYCWCVDPEGQEIPGTRtRGGDPDC 66

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 568955021  212 RACSDLEFREVANRLRDWFKALHESGSQNKKTKALLRPERSRFDTSILPICKDSLGWMFNRLDTNYDLLLDQSELGSIY- 290
Cdd:pfam10591   1 PCCTDEELAEFPRRMRDWLKLLLEALRNRRERKDHSSTLEKRDESLLYPCCKDPLGWMFKRLDTNDDLLLDHEELAPIRa 80

                          90       100       110
                  ....*....|....*....|....*....|.
gi 568955021  291 -LDKNEQCTKAFFNSCDTYKDSLISNNEWCY 320
Cdd:pfam10591  81 pLKPEEHCIKPFFESCDANKDKLISLEEWCC 111

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 568955021 329 PCHTELSNIQKRQGIKKLLGQYIPLCDEDGYYKPTQCHGSVGQCWCVDRYGNEVVGSRI-NGVADC 393
Cdd:cd00191    1 PCERERASALESLAGPKLSGLYVPQCDEDGNYEPVQCHGSTGYCWCVDPDGEEIPGTRTrGGPPNC 66

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 568955021  150 STCKPCPIAYASPVCGSDGHSYSSQCKLEYQACVLGKQIS---IKCEGRC 196
Cdd:pfam07648   1 NCNCQCPKTEYEPVCGSDGVTYPSPCALCAAGCKLGKEVKeekVKYDGSC 50

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 568955021 155 CPIAYaSPVCGSDGHSYSSQCKLEYQACVLGKQISIKCEGRC 196
Cdd:cd00104    1 CPKEY-DPVCGSDGKTYSNECHLGCAACRSGRSITVAHNGPC 41

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 568955021 214 CSDLEFREVANRLRDWFKALHESGSQNKKTKALLRpersrFDTSILPICKDSLGWMFNRLDTNYDLLLDQSELGSIYLDK 293
Cdd:cd16232    1 CTESELSEMGDRLLDWFSVLHEQSNKAKKTSSSKR-----FDKSHLPECKPSVGWMFNQLDTNNDLHLSQSELYDLELDK 75

                         90       100       110
                 ....*....|....*....|....*....|...
gi 568955021 294 NEQCTKAFFNSCDTYKDSLISNNEWCYCFQRQQ 326
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 568955021  212 RACSDLEFREVANRLRDWFKALHESGSQNKKTKALLRPERSRFDTSILPICKDSLGWMFNRLDTNYDLLLDQSELGSIY- 290
Cdd:pfam10591   1 PCCTDEELAEFPRRMRDWLKLLLEALRNRRERKDHSSTLEKRDESLLYPCCKDPLGWMFKRLDTNDDLLLDHEELAPIRa 80

                          90       100       110
                  ....*....|....*....|....*....|.
gi 568955021  291 -LDKNEQCTKAFFNSCDTYKDSLISNNEWCY 320
Cdd:pfam10591  81 pLKPEEHCIKPFFESCDANKDKLISLEEWCC 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 568955021  330 CHTELSNIQKR-QGIKKLLGQYIPLCDEDGYYKPTQCHGSVGQCWCVDRYGNEVVGSR-INGVADC 393
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 568955021 214 CSDLEFREVANRLRDWFKALHESGSQNKKTKALLRPERSRFDtsilpiCKDSLGWMFNRLDTNYDLLLDQSELGSI--YL 291
Cdd:cd00252    1 CPGSELMQFPDRLLDWLLLLKEQDENRSYDNNKRGHDLSGTM------RKEIAQWEFDNLDNNKDGKLDKRELAPFraPL 74

                         90       100       110
                 ....*....|....*....|....*....|.
gi 568955021 292 DKNEQCTKAFFNSCDTYKDSLISNNEWCYCF 322
Cdd:cd00252   75 MPLEHCARGFFESCDLNKDKKISLQEWLGCF 105

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 568955021 214 CSDLEFREVANRLRDWFK-------ALHESGsqNKKTKALLRPERSRFDTSILPICkdslgWMFNRLDTN-YDLLLDQSE 285
Cdd:cd16231    1 CLDEELSEFPLRMRDWLKnvmvqlaERDELH--EGLTEKELEDFQKNYKMYVYPVH-----WKFCDLDQHpHDRYLSHHE 73

                         90       100       110
                 ....*....|....*....|....*....|....*....
gi 568955021 286 LGSIY--LDKNEQCTKAFFNSCDTYKDSLISNNEWCYCF 322
Cdd:cd16231   74 LAPLRapLVPMEHCTTPFLETCDADNDKLISLKEWGACL 112

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

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....
gi 568955021   153 KPCPIAYaSPVCGSDGHSYSSQCKLEYQACVLGKQISIKCEGRC 196
Cdd:smart00280   4 EACPREY-DPVCGSDGVTYSNECHLCKAACESGKSIEVKHDGPC 46

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        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568955021 214 CSDLEFREVANRLRDWFKALhesgsqnkktkaLLRPersrfdTSILPIckdslGWMFNRLDTN-YDLLLDQSELGSIY-- 290
Cdd:cd16236    1 CTDSEVVQFPLRMRDWLKNI------------LMQL------YYIYPV-----HWQFAQLDQHpSDRFLTHSELAPLRas 57

                         90       100       110
                 ....*....|....*....|....*....|..
gi 568955021 291 LDKNEQCTKAFFNSCDTYKDSLISNNEWCYCF 322
Cdd:cd16236   58 LVPMEHCITRFFQECDADKDKLITLKEWCHCF 89

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        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568955021 214 CSDLEFREVANRLRDWFKALhesgsqnkktkALLRPERSRfdtsILPIckdslGWMFNRLDTN-YDLLLDQSELGSIY-- 290
Cdd:cd16235    1 CLDSELTEFPLRMRDWLKNV-----------LVTLYERDY----IFPV-----HWQFGQLDQHpIDGYLSHTELAPLRap 60

                         90       100       110
                 ....*....|....*....|....*....|..
gi 568955021 291 LDKNEQCTKAFFNSCDTYKDSLISNNEWCYCF 322
Cdd:cd16235   61 LIPMEHCTTRFFETCDLDNDKYIALDEWAGCF 92