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 281362337 428 CKPQQLTAIGNRLLDWFSVIMADSKKRRQHSQ--KSKAHFPPACKTEAKWMFGHLDLNNDGQLSLQEMYDLEHDQNERCI 505
Cdd:cd16232    1 CTESELSEMGDRLLDWFSVLHEQSNKAKKTSSskRFDKSHLPECKPSVGWMFNQLDTNNDLHLSQSELYDLELDKYEPCI 80

                         90       100
                 ....*....|....*....|....*...
gi 281362337 506 KPFIDTCDLDTDSSINTREWCRCFEKTD 533
Cdd:cd16232   81 KPFLDSCDRNKDGKISSDEWCDCFQRAD 108

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

                           10        20        30
                   ....*....|....*....|....*....|...
gi 281362337   240 CGADNRTYSSLCRLDYHNCIHSTSIRIACKGFC 272
Cdd:smart00280  14 CGSDGVTYSNECHLCKAACESGKSIEVKHDGPC 46

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 281362337 428 CKPQQLTAIGNRLLDWFSVIMADSKKRRQHSQ--KSKAHFPPACKTEAKWMFGHLDLNNDGQLSLQEMYDLEHDQNERCI 505
Cdd:cd16232    1 CTESELSEMGDRLLDWFSVLHEQSNKAKKTSSskRFDKSHLPECKPSVGWMFNQLDTNNDLHLSQSELYDLELDKYEPCI 80

                         90       100
                 ....*....|....*....|....*...
gi 281362337 506 KPFIDTCDLDTDSSINTREWCRCFEKTD 533
Cdd:cd16232   81 KPFLDSCDRNKDGKISSDEWCDCFQRAD 108

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
                  ....*....|....*....|....*....|....*....|....*....
gi 281362337  547 FAGAYAPDCDIQGFYKPTQCHNSVGVCWCVDKHGVEFANTRTR-GKPNC 594
Cdd:pfam00086  18 ASGLYIPNCDEDGFYKPVQCHGSTGYCWCVDPEGQEIPGTRTRgGDPDC 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 281362337   553 PDCDIQGFYKPTQCHNSVGVCWCVDKHGVEFANTRT-RGKPNCES 596
Cdd:smart00211   2 PQCDEDGNYEPVQCDGSSGQCWCVDATGREIPGTRTeGGDPDCPS 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
                  ....*....|....*....|....*....|....*....|....*...
gi 281362337  228 CKPCPVAKPTFLCGADNRTYSSLCRLDYHNCIHSTSIR---IACKGFC 272
Cdd:pfam07648   3 NCQCPKTEYEPVCGSDGVTYPSPCALCAAGCKLGKEVKeekVKYDGSC 50

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 281362337 428 CKPQQLTAIGNRLLDWFSVIMADSKKRRQHSQ--KSKAHFPPACKTEAKWMFGHLDLNNDGQLSLQEMYDLEHDQNERCI 505
Cdd:cd16232    1 CTESELSEMGDRLLDWFSVLHEQSNKAKKTSSskRFDKSHLPECKPSVGWMFNQLDTNNDLHLSQSELYDLELDKYEPCI 80

                         90       100
                 ....*....|....*....|....*...
gi 281362337 506 KPFIDTCDLDTDSSINTREWCRCFEKTD 533
Cdd:cd16232   81 KPFLDSCDRNKDGKISSDEWCDCFQRAD 108

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
                  ....*....|....*....|....*....|....*....|....*....
gi 281362337  547 FAGAYAPDCDIQGFYKPTQCHNSVGVCWCVDKHGVEFANTRTR-GKPNC 594
Cdd:pfam00086  18 ASGLYIPNCDEDGFYKPVQCHGSTGYCWCVDPEGQEIPGTRTRgGDPDC 66

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        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 281362337 428 CKPQQLTAIGNRLLDWFSVIMADSKK--RRQHSQKSKAHFP----PACKTEAKWMFGHLDLNNDGQLSLQEMYDLEHDQN 501
Cdd:cd16237    1 CTDKELRNLASRLKDWFGALHEDANRviKPTSSFTAQGRFDtsilPICKDSLGWMFNKLDMNYDLLLDPSEISAIYLDKY 80

                         90       100       110
                 ....*....|....*....|....*....|
gi 281362337 502 ERCIKPFIDTCDLDTDSSINTREWCRCFEK 531
Cdd:cd16237   81 EPCMKPLFNSCDSFKDGKLSNNEWCYCFQK 110

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 281362337  427 ECKPQQLTAIGNRLLDWFSVIMADSKKRRQ---HSQKSKAHF----PPACKTEAKWMFGHLDLNNDGQLSLQEM--YDLE 497
Cdd:pfam10591   2 CCTDEELAEFPRRMRDWLKLLLEALRNRRErkdHSSTLEKRDesllYPCCKDPLGWMFKRLDTNDDLLLDHEELapIRAP 81

                          90       100       110
                  ....*....|....*....|....*....|
gi 281362337  498 HDQNERCIKPFIDTCDLDTDSSINTREWCR 527
Cdd:pfam10591  82 LKPEEHCIKPFFESCDANKDKLISLEEWCC 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 and binding partners of heparin.

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*
gi 281362337   553 PDCDIQGFYKPTQCHNSVGVCWCVDKHGVEFANTRT-RGKPNCES 596
Cdd:smart00211   2 PQCDEDGNYEPVQCDGSSGQCWCVDATGREIPGTRTeGGDPDCPS 46

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 281362337 428 CKPQQLTAIGNRLLDWFSVIMADSKKRrqhsqksKAHFPpackteAKWMFGHLDLNN-DGQLSLQEMYDLEHD--QNERC 504
Cdd:cd16235    1 CLDSELTEFPLRMRDWLKNVLVTLYER-------DYIFP------VHWQFGQLDQHPiDGYLSHTELAPLRAPliPMEHC 67

                         90       100
                 ....*....|....*....|....*
gi 281362337 505 IKPFIDTCDLDTDSSINTREWCRCF 529
Cdd:cd16235   68 TTRFFETCDLDNDKYIALDEWAGCF 92

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 281362337 455 RQHSQKSKAHFPPACKTEAKWMFGHLDLNNDGQLSLQEMYDL-----EHDQNERCIKPFIDTCDLDTDSSINTREWCRCF 529
Cdd:cd16234   23 RSGNSNSSAPDKSSEEQVLDWKFSQLDKNKNGVLERKEWKPFkrllkKAVKPKKCARKFPKYCDVNKDKKISLTEWLNCL 102

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
                  ....*....|....*....|....*....|....*....|....*...
gi 281362337  228 CKPCPVAKPTFLCGADNRTYSSLCRLDYHNCIHSTSIR---IACKGFC 272
Cdd:pfam07648   3 NCQCPKTEYEPVCGSDGVTYPSPCALCAAGCKLGKEVKeekVKYDGSC 50

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
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 281362337 475 WMFGHLDLN-NDGQLSLQEMYDLEHD--QNERCIKPFIDTCDLDTDSSINTREWCRCF 529
Cdd:cd16236   32 WQFAQLDQHpSDRFLTHSELAPLRASlvPMEHCITRFFQECDADKDKLITLKEWCHCF 89