EF-hand, extracellular calcium-binding (EC) motif, found in testican-3 (TICN3); TICN3, also termed SPARC/osteonectin, CWCV, and Kazal-like domains proteoglycan 3 (Spock3), is a brain-specific heparan sulfate proteoglycan that shows a widespread distribution within the extracellular matrix of the brain. It plays an important role in the formation or maintenance of major neuronal structures in the brain. It also functions as a novel regulator to reduce the activity of matrix metalloproteinase (MMP) in adult T-cell leukemia (ATL). It suppresses membrane-type 1 MMP-mediated MMP-2 activation and tumor invasion. Moreover, TICN3 corresponding gene SPOCK3 acts as a risk gene for adult attention-deficit/hyperactivity disorder (ADHD) and personality disorders. TICN3 contains an N-terminal signal peptide, a testican-specific domain followed by the follistatin-like (FS) and extracellular calcium-binding (EC) domains characteristic of the BM-40 family. Towards the C-terminus they contain a thyroglobulin-like domain (TY) and a novel sequence (domain V), which includes two potential glycosaminoglycan attachment sites. The substitution of a ligating Asp residue by Tyr295 in the +Y position of EF-hand 2 in testican-3 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 324072875 198 CSDLEFREVANRLRDWFKALHESGSQNKKTKTLLRPERSRFDTSILPICKDSLGWMFNRLDTNYDLLLDQSELRSIYLDK 277
Cdd:cd16239    1 CSDLEFREVANRLRDWFKALHESGSQNKKTKIVRRPERSRFDTSILPICKDSLGWMFNRLDTNYDLLLDQSELGSIYLDK 80

                         90       100       110
                 ....*....|....*....|....*....|...
gi 324072875 278 NEQCTKAFFNSCDTYKDSLISNNEWCYCFQRQQ 310
Cdd:cd16239   81 NEQCTKAFFNSCDTYKDSLISNNEWCYCFQRQQ 113

EF-hand, extracellular calcium-binding (EC) motif, found in testican-3 (TICN3); TICN3, also termed SPARC/osteonectin, CWCV, and Kazal-like domains proteoglycan 3 (Spock3), is a brain-specific heparan sulfate proteoglycan that shows a widespread distribution within the extracellular matrix of the brain. It plays an important role in the formation or maintenance of major neuronal structures in the brain. It also functions as a novel regulator to reduce the activity of matrix metalloproteinase (MMP) in adult T-cell leukemia (ATL). It suppresses membrane-type 1 MMP-mediated MMP-2 activation and tumor invasion. Moreover, TICN3 corresponding gene SPOCK3 acts as a risk gene for adult attention-deficit/hyperactivity disorder (ADHD) and personality disorders. TICN3 contains an N-terminal signal peptide, a testican-specific domain followed by the follistatin-like (FS) and extracellular calcium-binding (EC) domains characteristic of the BM-40 family. Towards the C-terminus they contain a thyroglobulin-like domain (TY) and a novel sequence (domain V), which includes two potential glycosaminoglycan attachment sites. The substitution of a ligating Asp residue by Tyr295 in the +Y position of EF-hand 2 in testican-3 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 324072875 198 CSDLEFREVANRLRDWFKALHESGSQNKKTKTLLRPERSRFDTSILPICKDSLGWMFNRLDTNYDLLLDQSELRSIYLDK 277
Cdd:cd16239    1 CSDLEFREVANRLRDWFKALHESGSQNKKTKIVRRPERSRFDTSILPICKDSLGWMFNRLDTNYDLLLDQSELGSIYLDK 80

                         90       100       110
                 ....*....|....*....|....*....|...
gi 324072875 278 NEQCTKAFFNSCDTYKDSLISNNEWCYCFQRQQ 310
Cdd:cd16239   81 NEQCTKAFFNSCDTYKDSLISNNEWCYCFQRQQ 113

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

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....
gi 324072875   137 KQCPVVYpSPVCGSDGHTYSFQCKLEYQACVLGKQISVKCEGHC 180
Cdd:smart00280   4 EACPREY-DPVCGSDGVTYSNECHLCKAACESGKSIEVKHDGPC 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 324072875 139 CPVVYpSPVCGSDGHTYSFQCKLEYQACVLGKQISVKCEGHC 180
Cdd:cd00104    1 CPKEY-DPVCGSDGKTYSNECHLGCAACRSGRSITVAHNGPC 41

EF-hand, extracellular calcium-binding (EC) motif, found in testican-3 (TICN3); TICN3, also termed SPARC/osteonectin, CWCV, and Kazal-like domains proteoglycan 3 (Spock3), is a brain-specific heparan sulfate proteoglycan that shows a widespread distribution within the extracellular matrix of the brain. It plays an important role in the formation or maintenance of major neuronal structures in the brain. It also functions as a novel regulator to reduce the activity of matrix metalloproteinase (MMP) in adult T-cell leukemia (ATL). It suppresses membrane-type 1 MMP-mediated MMP-2 activation and tumor invasion. Moreover, TICN3 corresponding gene SPOCK3 acts as a risk gene for adult attention-deficit/hyperactivity disorder (ADHD) and personality disorders. TICN3 contains an N-terminal signal peptide, a testican-specific domain followed by the follistatin-like (FS) and extracellular calcium-binding (EC) domains characteristic of the BM-40 family. Towards the C-terminus they contain a thyroglobulin-like domain (TY) and a novel sequence (domain V), which includes two potential glycosaminoglycan attachment sites. The substitution of a ligating Asp residue by Tyr295 in the +Y position of EF-hand 2 in testican-3 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 324072875 198 CSDLEFREVANRLRDWFKALHESGSQNKKTKTLLRPERSRFDTSILPICKDSLGWMFNRLDTNYDLLLDQSELRSIYLDK 277
Cdd:cd16239    1 CSDLEFREVANRLRDWFKALHESGSQNKKTKIVRRPERSRFDTSILPICKDSLGWMFNRLDTNYDLLLDQSELGSIYLDK 80

                         90       100       110
                 ....*....|....*....|....*....|...
gi 324072875 278 NEQCTKAFFNSCDTYKDSLISNNEWCYCFQRQQ 310
Cdd:cd16239   81 NEQCTKAFFNSCDTYKDSLISNNEWCYCFQRQQ 113

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 324072875 198 CSDLEFREVANRLRDWFKALHESGSQNKKTkTLLRPERSRFDTSILPICKDSLGWMFNRLDTNYDLLLDQSELRSIYLDK 277
Cdd:cd16237    1 CTDKELRNLASRLKDWFGALHEDANRVIKP-TSSFTAQGRFDTSILPICKDSLGWMFNKLDMNYDLLLDPSEISAIYLDK 79

                         90       100       110
                 ....*....|....*....|....*....|.
gi 324072875 278 NEQCTKAFFNSCDTYKDSLISNNEWCYCFQR 308
Cdd:cd16237   80 YEPCMKPLFNSCDSFKDGKLSNNEWCYCFQK 110

EF-hand, extracellular calcium-binding (EC) motif, found in testican-2 (TICN2); TICN2, also termed SPARC/osteonectin, CWCV, and Kazal-like domains proteoglycan 2 (Spock2), is an extracellular heparan sulphate proteoglycan expressed in brain, lung, and testis. It inhibits neurite extension from cultured primary cerebellar neurons and may play regulatory roles in the development of the central nervous system. It also participates in diverse steps of neurogenesis. Moreover, TICN2 may contribute to ECM remodeling by regulating function(s) of other testican family members, which possess membrane-type matrix metalloproteinases (MT-MMPs) inhibitory function. Furthermore, TICN2 corresponding gene SPOCK2 acts as a susceptibility gene for bronchopulmonary dysplasia. TICN2 contains 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 Tyr292 in the +Y position of EF-hand 2 in TICN2 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 324072875 198 CSDLEFREVANRLRDWFKALHESGSQNKkTKTLLRPERSRFDTSILPICKDSLGWMFNRLDTNYDLLLDQSELRSIYLDK 277
Cdd:cd16238    1 CTGQDLADLGDRLRDWFQLLHENSKQNG-SGSPPASPASALDRSLVASCKDSIGWMFSKLDTSGDLFLDQAELAAINLDK 79

                         90       100       110
                 ....*....|....*....|....*....|...
gi 324072875 278 NEQCTKAFFNSCDTYKDSLISNNEWCYCFQRQQ 310
Cdd:cd16238   80 YEVCIRPFFNSCDTYRDGRVSTAEWCFCFWREK 112

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 324072875 198 CSDLEFREVANRLRDWFK-------ALHESGsqNKKTKTLLRPERSRFDTSILPICkdslgWMFNRLDTN-YDLLLDQSE 269
Cdd:cd16231    1 CLDEELSEFPLRMRDWLKnvmvqlaERDELH--EGLTEKELEDFQKNYKMYVYPVH-----WKFCDLDQHpHDRYLSHHE 73

                         90       100       110
                 ....*....|....*....|....*....|....*....
gi 324072875 270 LRSIY--LDKNEQCTKAFFNSCDTYKDSLISNNEWCYCF 306
Cdd:cd16231   74 LAPLRapLVPMEHCTTPFLETCDADNDKLISLKEWGACL 112

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 324072875  134 STCKQCPVVYPSPVCGSDGHTYSFQCKLEYQACVLGKQIS---VKCEGHC 180
Cdd:pfam07648   1 NCNCQCPKTEYEPVCGSDGVTYPSPCALCAAGCKLGKEVKeekVKYDGSC 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        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 324072875 198 CSDLEFREVANRLRDWFKALhesgsqnkktktLLRPersrfdTSILPIckdslGWMFNRLDTN-YDLLLDQSELRSIY-- 274
Cdd:cd16236    1 CTDSEVVQFPLRMRDWLKNI------------LMQL------YYIYPV-----HWQFAQLDQHpSDRFLTHSELAPLRas 57

                         90       100       110
                 ....*....|....*....|....*....|..
gi 324072875 275 LDKNEQCTKAFFNSCDTYKDSLISNNEWCYCF 306
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 324072875 198 CSDLEFREVANRLRDWFKALhesgsqnkkTKTLLrpERSrfdtSILPIckdslGWMFNRLDTN-YDLLLDQSELRSIY-- 274
Cdd:cd16235    1 CLDSELTEFPLRMRDWLKNV---------LVTLY--ERD----YIFPV-----HWQFGQLDQHpIDGYLSHTELAPLRap 60

                         90       100       110
                 ....*....|....*....|....*....|..
gi 324072875 275 LDKNEQCTKAFFNSCDTYKDSLISNNEWCYCF 306
Cdd:cd16235   61 LIPMEHCTTRFFETCDLDNDKYIALDEWAGCF 92

EF-hand, calcium binding motif; A diverse superfamily of calcium sensors and calcium signal modulators; most examples in this alignment model have 2 active canonical EF hands. Ca2+ binding induces a conformational change in the EF-hand motif, leading to the activation or inactivation of target proteins. EF-hands tend to occur in pairs or higher copy numbers.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 324072875 252 WMFNRLDTNYDLLLDQSELR----SIYLDKNEQCTKAFFNSCDTYKDSLISNNEWC 303
Cdd:cd00051    4 EAFRLFDKDGDGTISADELKaalkSLGEGLSEEEIDEMIREVDKDGDGKIDFEEFL 59