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 4759164  198 CTDKELRNLASRLKDWFGALHEDANRVIKPTSSNTAQGRFDTSILPICKDSLGWMFNKLDMNYDLLLDPSEINAIYLDKY 277
Cdd:cd16237   1 CTDKELRNLASRLKDWFGALHEDANRVIKPTSSFTAQGRFDTSILPICKDSLGWMFNKLDMNYDLLLDPSEISAIYLDKY 80

                        90       100       110
                ....*....|....*....|....*....|..
gi 4759164  278 EPCIKPLFNSCDSFKDGKLSNNEWCYCFQKPG 309
Cdd:cd16237  81 EPCMKPLFNSCDSFKDGKLSNNEWCYCFQKPG 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
                  ....*....|....*....|....*....|....*....
gi 4759164    136 CKPCPVAQSAMVCGSDGHSYTSKCKLEFHACSTGKSLAT 174
Cdd:pfam07648   3 NCQCPKTEYEPVCGSDGVTYPSPCALCAAGCKLGKEVKE 41

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 4759164  198 CTDKELRNLASRLKDWFGALHEDANRVIKPTSSNTAQGRFDTSILPICKDSLGWMFNKLDMNYDLLLDPSEINAIYLDKY 277
Cdd:cd16237   1 CTDKELRNLASRLKDWFGALHEDANRVIKPTSSFTAQGRFDTSILPICKDSLGWMFNKLDMNYDLLLDPSEISAIYLDKY 80

                        90       100       110
                ....*....|....*....|....*....|..
gi 4759164  278 EPCIKPLFNSCDSFKDGKLSNNEWCYCFQKPG 309
Cdd:cd16237  81 EPCMKPLFNSCDSFKDGKLSNNEWCYCFQKPG 112

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 4759164  312 PCQNEMNRIQKLSKGKSLLGAFIPRCNEEGYYKATQCHGSTGQCWCVDKYGNELAGSRKQG 372
Cdd:cd00191   1 PCERERASALESLAGPKLSGLYVPQCDEDGNYEPVQCHGSTGYCWCVDPDGEEIPGTRTRG 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 4759164     334 IPRCNEEGYYKATQCHGSTGQCWCVDKYGNELAGSRKQGAV-SCEE 378
Cdd:smart00211   1 IPQCDEDGNYEPVQCDGSSGQCWCVDATGREIPGTRTEGGDpDCPS 46

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

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|..
gi 4759164     137 KPCPVAqSAMVCGSDGHSYTSKCKLEFHACSTGKSLATLCDG 178
Cdd:smart00280   4 EACPRE-YDPVCGSDGVTYSNECHLCKAACESGKSIEVKHDG 44

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 4759164  198 CTDKELRNLASRLKDWFGALHEDANRVIKPTSSNTAQGRFDTSILPICKDSLGWMFNKLDMNYDLLLDPSEINAIYLDKY 277
Cdd:cd16237   1 CTDKELRNLASRLKDWFGALHEDANRVIKPTSSFTAQGRFDTSILPICKDSLGWMFNKLDMNYDLLLDPSEISAIYLDKY 80

                        90       100       110
                ....*....|....*....|....*....|..
gi 4759164  278 EPCIKPLFNSCDSFKDGKLSNNEWCYCFQKPG 309
Cdd:cd16237  81 EPCMKPLFNSCDSFKDGKLSNNEWCYCFQKPG 112

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 4759164  198 CTDKELRNLASRLKDWFGALHEDA--NRVIKpTSSNTAQGRFDTSILPICKDSLGWMFNKLDMNYDLLLDPSEINAIYLD 275
Cdd:cd16239   1 CSDLEFREVANRLRDWFKALHESGsqNKKTK-IVRRPERSRFDTSILPICKDSLGWMFNRLDTNYDLLLDQSELGSIYLD 79

                        90       100       110
                ....*....|....*....|....*....|..
gi 4759164  276 KYEPCIKPLFNSCDSFKDGKLSNNEWCYCFQK 307
Cdd:cd16239  80 KNEQCTKAFFNSCDTYKDSLISNNEWCYCFQR 111

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 4759164  198 CTDKELRNLASRLKDWFGALHEDANRVIKPTSSNTAQGRFDTSILPICKDSLGWMFNKLDMNYDLLLDPSEINAIYLDKY 277
Cdd:cd16238   1 CTGQDLADLGDRLRDWFQLLHENSKQNGSGSPPASPASALDRSLVASCKDSIGWMFSKLDTSGDLFLDQAELAAINLDKY 80

                        90       100
                ....*....|....*....|....*...
gi 4759164  278 EPCIKPLFNSCDSFKDGKLSNNEWCYCF 305
Cdd:cd16238  81 EVCIRPFFNSCDTYRDGRVSTAEWCFCF 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        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 4759164    313 CQNEMNRIQK-LSKGKSLLGAFIPRCNEEGYYKATQCHGSTGQCWCVDKYGNELAGSRKQGA 373
Cdd:pfam00086   1 CERERARALEqAASGRPASGLYIPNCDEDGFYKPVQCHGSTGYCWCVDPEGQEIPGTRTRGG 62

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 4759164     334 IPRCNEEGYYKATQCHGSTGQCWCVDKYGNELAGSRKQGAV-SCEE 378
Cdd:smart00211   1 IPQCDEDGNYEPVQCDGSSGQCWCVDATGREIPGTRTEGGDpDCPS 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
                  ....*....|....*....|....*....|....*....
gi 4759164    136 CKPCPVAQSAMVCGSDGHSYTSKCKLEFHACSTGKSLAT 174
Cdd:pfam07648   3 NCQCPKTEYEPVCGSDGVTYPSPCALCAAGCKLGKEVKE 41

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 4759164  198 CTDKELRNLASRLKDWFgalhedanrvikptsSNTAQGRFdtSILPIckdslGWMFNKLDMN-YDLLLDPSEINAIY--L 274
Cdd:cd16236   1 CTDSEVVQFPLRMRDWL---------------KNILMQLY--YIYPV-----HWQFAQLDQHpSDRFLTHSELAPLRasL 58

                        90       100       110
                ....*....|....*....|....*....|.
gi 4759164  275 DKYEPCIKPLFNSCDSFKDGKLSNNEWCYCF 305
Cdd:cd16236  59 VPMEHCITRFFQECDADKDKLITLKEWCHCF 89

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 4759164  251 WMFNKLDMNYDLLLDPSEI--------NAIYLDKyepCIKPLFNSCDSFKDGKLSNNEWCYCFQK 307
Cdd:cd16234  43 WKFSQLDKNKNGVLERKEWkpfkrllkKAVKPKK---CARKFPKYCDVNKDKKISLTEWLNCLGV 104