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 16184904 182 CSKSDRSQFNTNLMRMFRNEAQSFFRQPSL-----SDSHILEWQFSKLDTNGNKLLDRQEIRELKKVLRRNVKPRRCGRT 256
Cdd:cd16234   1 CPEAKKTEFLNNLIDALKTEMVRSGNSNSSapdksSEEQVLDWKFSQLDKNKNGVLERKEWKPFKRLLKKAVKPKKCARK 80

                        90       100
                ....*....|....*....|....
gi 16184904 257 FGKYCDVTKDANLNWLEWSVCFTK 280
Cdd:cd16234  81 FPKYCDVNKDKKISLTEWLNCLGV 104

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
                ....*....|....*....|....*....|....*....|....*....|...
gi 16184904  88 RRQQERDPGYFVPRCRKDGNFAAMQCYGNNG-CWCSDSQGRPIADDNKQFRRK 139
Cdd:cd00191  12 SLAGPKLSGLYVPQCDEDGNYEPVQCHGSTGyCWCVDPDGEEIPGTRTRGGPP 64

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 16184904 182 CSKSDRSQFNTNLMRMFRNEAQSFFRQPSL-----SDSHILEWQFSKLDTNGNKLLDRQEIRELKKVLRRNVKPRRCGRT 256
Cdd:cd16234   1 CPEAKKTEFLNNLIDALKTEMVRSGNSNSSapdksSEEQVLDWKFSQLDKNKNGVLERKEWKPFKRLLKKAVKPKKCARK 80

                        90       100
                ....*....|....*....|....
gi 16184904 257 FGKYCDVTKDANLNWLEWSVCFTK 280
Cdd:cd16234  81 FPKYCDVNKDKKISLTEWLNCLGV 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 16184904   400 QSVTLEEQGHGGKSVLFVPQCLPDGRYQRIQCYSstSTSYCWCVNEDtGKSIPGTSVKNKRPQC 463
Cdd:pfam00086   6 ARALEQAASGRPASGLYIPNCDEDGFYKPVQCHG--STGYCWCVDPE-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 16184904    417 VPQCLPDGRYQRIQCYssTSTSYCWCVNEdTGKSIPGTSVKNKRPQCDE 465
Cdd:smart00211   1 IPQCDEDGNYEPVQCD--GSSGQCWCVDA-TGREIPGTRTEGGDPDCPS 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 16184904  38 CDDNEGPVCGTDGQTYPTRCHLLRAQC-GGHQVSLKYSGSC 77
Cdd:cd00104   1 CPKEYDPVCGSDGKTYSNECHLGCAACrSGRSITVAHNGPC 41

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
                   ....*....|....*....|....*....|....
gi 16184904     99 VPRCRKDGNFAAMQCYGNNG-CWCSDSQGRPIAD 131
Cdd:smart00211   1 IPQCDEDGNYEPVQCDGSSGqCWCVDATGREIPG 34

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 16184904   198 FRNEAQSFFRQ--PSLSDShILEWQFSKLDTNGNKLLDRQEIRELKKVLrrnVKPRRCGRTFGKYCDVTKDANLNWLEW 274
Cdd:pfam10591  35 HSSTLEKRDESllYPCCKD-PLGWMFKRLDTNDDLLLDHEELAPIRAPL---KPEEHCIKPFFESCDANKDKLISLEEW 109

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 16184904 182 CSKSDRSQFNTNLMRMFRNEAQSFFRQPSL-----SDSHILEWQFSKLDTNGNKLLDRQEIRELKKVLRRNVKPRRCGRT 256
Cdd:cd16234   1 CPEAKKTEFLNNLIDALKTEMVRSGNSNSSapdksSEEQVLDWKFSQLDKNKNGVLERKEWKPFKRLLKKAVKPKKCARK 80

                        90       100
                ....*....|....*....|....
gi 16184904 257 FGKYCDVTKDANLNWLEWSVCFTK 280
Cdd:cd16234  81 FPKYCDVNKDKKISLTEWLNCLGV 104

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 16184904 475 CTEPRKTQFLKELKAYLNTSLLPSSTTGSNSSMRKTD-------DERIATLSFVYLDKNKNKSWDRREWKNFRDLVTSAS 547
Cdd:cd16241   1 CPGAKKTEFLTSVLDALSTDMVHAVSDPSASSRRLSEpdpshtlEERVVHWYFKQLDKNSSGDIGKKEIKPFKRFLRKKS 80

                        90       100       110
                ....*....|....*....|....*....|...
gi 16184904 548 HLRRCGKKMPRYCDVNGDKKISLAEWLNCLQAT 580
Cdd:cd16241  81 KPKKCVKKFVEYCDVNNDKSLSVQELMGCLGVT 113

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 16184904 182 CSKSDRSQFNTNLMRMF-----RNEAQSFFRQPSLSD------SHILEWQFSKLDTNGNKLLDRqeiRELKKVLRRNVKP 250
Cdd:cd00252   1 CPGSELMQFPDRLLDWLlllkeQDENRSYDNNKRGHDlsgtmrKEIAQWEFDNLDNNKDGKLDK---RELAPFRAPLMPL 77

                        90       100
                ....*....|....*....|....*....
gi 16184904 251 RRCGRTFGKYCDVTKDANLNWLEWSVCFT 279
Cdd:cd00252  78 EHCARGFFESCDLNKDKKISLQEWLGCFG 106

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 16184904 182 CSKSDRSQFNTNLMRMFRNEAQSFFRQPSLSD--------SHILE-----WQFSKLDTNGNKLLDRQEIRELKKVLRRNV 248
Cdd:cd16241   1 CPGAKKTEFLTSVLDALSTDMVHAVSDPSASSrrlsepdpSHTLEervvhWYFKQLDKNSSGDIGKKEIKPFKRFLRKKS 80

                        90       100       110
                ....*....|....*....|....*....|
gi 16184904 249 KPRRCGRTFGKYCDVTKDANLNWLEWSVCF 278
Cdd:cd16241  81 KPKKCVKKFVEYCDVNNDKSLSVQELMGCL 110

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 16184904    417 VPQCLPDGRYQRIQCYssTSTSYCWCVNEdTGKSIPGTSVKNKRPQCDE 465
Cdd:smart00211   1 IPQCDEDGNYEPVQCD--GSSGQCWCVDA-TGREIPGTRTEGGDPDCPS 46

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 16184904 475 CTEPRKTQFLKELKAYLNTSLLPS-----STTGSNSSMRKTDDERIATLSFVYLDKNKNKSWDRREWKNFRDLVTSashL 549
Cdd:cd00252   1 CPGSELMQFPDRLLDWLLLLKEQDenrsyDNNKRGHDLSGTMRKEIAQWEFDNLDNNKDGKLDKRELAPFRAPLMP---L 77

                        90       100
                ....*....|....*....|....*...
gi 16184904 550 RRCGKKMPRYCDVNGDKKISLAEWLNCL 577
Cdd:cd00252  78 EHCARGFFESCDLNKDKKISLQEWLGCF 105

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 16184904  38 CDDNEGPVCGTDGQTYPTRCHLLRAQC-GGHQVSLKYSGSC 77
Cdd:cd00104   1 CPKEYDPVCGSDGKTYSNECHLGCAACrSGRSITVAHNGPC 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 16184904 182 CSKSDRSQFNTNLMRMFR------NEAQSFFRQPSLSDSHILE------WQFSKLDTNGNKLLDRQEIRELKkvlrrNVK 249
Cdd:cd16232   1 CTESELSEMGDRLLDWFSvlheqsNKAKKTSSSKRFDKSHLPEckpsvgWMFNQLDTNNDLHLSQSELYDLE-----LDK 75

                        90       100       110
                ....*....|....*....|....*....|..
gi 16184904 250 PRRCGRTFGKYCDVTKDANLNWLEWSVCFTKE 281
Cdd:cd16232  76 YEPCIKPFLDSCDRNKDGKISSDEWCDCFQRA 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 and binding partners of heparin.

                           10        20        30
                   ....*....|....*....|....*....|....
gi 16184904     99 VPRCRKDGNFAAMQCYGNNG-CWCSDSQGRPIAD 131
Cdd:smart00211   1 IPQCDEDGNYEPVQCDGSSGqCWCVDATGREIPG 34

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 16184904   198 FRNEAQSFFRQ--PSLSDShILEWQFSKLDTNGNKLLDRQEIRELKKVLrrnVKPRRCGRTFGKYCDVTKDANLNWLEW 274
Cdd:pfam10591  35 HSSTLEKRDESllYPCCKD-PLGWMFKRLDTNDDLLLDHEELAPIRAPL---KPEEHCIKPFFESCDANKDKLISLEEW 109

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. Alignment also includes a single domain from transporters in the OATP/PGT family.

                          10        20        30
                  ....*....|....*....|....*....|....*.
gi 16184904    44 PVCGTDGQTYPTRCHL--LRAQcGGHQVSLKYSGSC 77
Cdd:pfam00050  15 PVCGTDGKTYSNECLFcaENGK-RGTNLHKVHDGEC 49

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 16184904 209 PSLSDShiLEWQFSKLDTNGNKLLDRQEIRELKKvlrrnVKPRRCGRTFGKYCDVTKDANLNWLEWSVCFTK 280
Cdd:cd16237  46 PICKDS--LGWMFNKLDMNYDLLLDPSEISAIYL-----DKYEPCMKPLFNSCDSFKDGKLSNNEWCYCFQK 110

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
                ....*....|....*....|....*....|....*....|....*....|....*....
gi 16184904 520 FVYLDKN-KNKSWDRREWKNFRDLVTSASHlrrCGKKMPRYCDVNGDKKISLAEWLNCL 577
Cdd:cd16231  57 FCDLDQHpHDRYLSHHELAPLRAPLVPMEH---CTTPFLETCDADNDKLISLKEWGACL 112