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 17541696 141 CTEEHMAQFPERMADWLFQVMKELKKRRELHKLEWEELLsEAENDDEKKHVYPVIWKFCELDTKPHDKSVSHHELIPITA 220
Cdd:cd16231   1 CLDEELSEFPLRMRDWLKNVMVQLAERDELHEGLTEKEL-EDFQKNYKMYVYPVHWKFCDLDQHPHDRYLSHHELAPLRA 79

                        90       100       110
                ....*....|....*....|....*....|....*..
gi 17541696 221 PVIPMESCIKPFLEGCDANNDGNISIKEWGKCLGLKE 257
Cdd:cd16231  80 PLVPMEHCTTPFLETCDADNDKLISLKEWGACLGLKE 116

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 17541696 141 CTEEHMAQFPERMADWLFQVMKELKKRRELHKLEWEELLsEAENDDEKKHVYPVIWKFCELDTKPHDKSVSHHELIPITA 220
Cdd:cd16231   1 CLDEELSEFPLRMRDWLKNVMVQLAERDELHEGLTEKEL-EDFQKNYKMYVYPVHWKFCDLDQHPHDRYLSHHELAPLRA 79

                        90       100       110
                ....*....|....*....|....*....|....*..
gi 17541696 221 PVIPMESCIKPFLEGCDANNDGNISIKEWGKCLGLKE 257
Cdd:cd16231  80 PLVPMEHCTTPFLETCDADNDKLISLKEWGACLGLKE 116

Follistatin-like SPARC (secreted protein, acidic, and rich in cysteines) domain; SPARC/BM-40/osteonectin is a multifunctional glycoprotein which modulates cellular interaction with the extracellular matrix by its binding to structural matrix proteins such as collagen and vitronectin. The protein it composed of an N-terminal acidic region, a follistatin (FS) domain and an EF-hand calcium binding domain. The FS domain consists of an N-terminal beta hairpin (FOLN/EGF-like domain) and a small hydrophobic core of alpha/beta structure (Kazal domain) and has five disulfide bonds and a conserved N-glycosylation site. The FSL_SPARC domain is a member of the superfamily of kazal-like proteinase inhibitors and follistatin-like proteins.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17541696  52 PCEDHQCGWGKECVVGKKGEPTCECISKCPELDGDPmDKVCANNNQTFTSLCDLYRERCLCKRKSKECSKAFNAKVHLEY 131
Cdd:cd01328   1 PCENHHCGAGKVCEVDDENTPKCVCIDPCPEEVDDR-RKVCTNDNETFDSDCELYRTRCLCKGGKKGCRGPKYQHLHLDY 79

                ....*..
gi 17541696 132 LGECKKL 138
Cdd:cd01328  80 YGECKEI 86

Follistatin-N-terminal domain-like; Follistatin-N-terminal domain-like, EGF-like. Region distinct from the kazal-like sequence

                           10        20
                   ....*....|....*....|....
gi 17541696     52 PCEDHQCGWGKECVVGKKGEPTCE 75
Cdd:smart00274   1 SCRNVQCPFGKVCVVDKNGNARCV 24

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 17541696 141 CTEEHMAQFPERMADWLFQVMKELKKRRELHKLEWEELLsEAENDDEKKHVYPVIWKFCELDTKPHDKSVSHHELIPITA 220
Cdd:cd16231   1 CLDEELSEFPLRMRDWLKNVMVQLAERDELHEGLTEKEL-EDFQKNYKMYVYPVHWKFCDLDQHPHDRYLSHHELAPLRA 79

                        90       100       110
                ....*....|....*....|....*....|....*..
gi 17541696 221 PVIPMESCIKPFLEGCDANNDGNISIKEWGKCLGLKE 257
Cdd:cd16231  80 PLVPMEHCTTPFLETCDADNDKLISLKEWGACLGLKE 116

Follistatin-like SPARC (secreted protein, acidic, and rich in cysteines) domain; SPARC/BM-40/osteonectin is a multifunctional glycoprotein which modulates cellular interaction with the extracellular matrix by its binding to structural matrix proteins such as collagen and vitronectin. The protein it composed of an N-terminal acidic region, a follistatin (FS) domain and an EF-hand calcium binding domain. The FS domain consists of an N-terminal beta hairpin (FOLN/EGF-like domain) and a small hydrophobic core of alpha/beta structure (Kazal domain) and has five disulfide bonds and a conserved N-glycosylation site. The FSL_SPARC domain is a member of the superfamily of kazal-like proteinase inhibitors and follistatin-like proteins.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17541696  52 PCEDHQCGWGKECVVGKKGEPTCECISKCPELDGDPmDKVCANNNQTFTSLCDLYRERCLCKRKSKECSKAFNAKVHLEY 131
Cdd:cd01328   1 PCENHHCGAGKVCEVDDENTPKCVCIDPCPEEVDDR-RKVCTNDNETFDSDCELYRTRCLCKGGKKGCRGPKYQHLHLDY 79

                ....*..
gi 17541696 132 LGECKKL 138
Cdd:cd01328  80 YGECKEI 86

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 17541696 141 CTEEHMAQFPERMADWLFQVMKELKkrrelhkleweellseaenddEKKHVYPVIWKFCELDTKPHDKSVSHHELIPITA 220
Cdd:cd16235   1 CLDSELTEFPLRMRDWLKNVLVTLY---------------------ERDYIFPVHWQFGQLDQHPIDGYLSHTELAPLRA 59

                        90       100       110
                ....*....|....*....|....*....|....*..
gi 17541696 221 PVIPMESCIKPFLEGCDANNDGNISIKEWGKCLGLKE 257
Cdd:cd16235  60 PLIPMEHCTTRFFETCDLDNDKYIALDEWAGCFGIKQ 96

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 17541696 141 CTEEHMAQFPERMADWlFQVMKELKKRRELHKLeweellseaeNDDEKKHVYP-----VIWKFCELDTKpHDKSVSHHEL 215
Cdd:cd16232   1 CTESELSEMGDRLLDW-FSVLHEQSNKAKKTSS----------SKRFDKSHLPeckpsVGWMFNQLDTN-NDLHLSQSEL 68

                        90       100       110
                ....*....|....*....|....*....|....*..
gi 17541696 216 IPITAPviPMESCIKPFLEGCDANNDGNISIKEWGKC 252
Cdd:cd16232  69 YDLELD--KYEPCIKPFLDSCDRNKDGKISSDEWCDC 103

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 17541696 194 VIWKFCELDtKPHDKSVSHHELIPITAPV---IPMESCIKPFLEGCDANNDGNISIKEWGKCLGL 255
Cdd:cd16234  41 LDWKFSQLD-KNKNGVLERKEWKPFKRLLkkaVKPKKCARKFPKYCDVNKDKKISLTEWLNCLGV 104

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 17541696 141 CTEEHMAQFPERMADWlFQVMKELKKRRELhklewEELLSEAENDDEKKHVY----PVIWKFCELDTKpHDKSVSHHELI 216
Cdd:cd16238   1 CTGQDLADLGDRLRDW-FQLLHENSKQNGS-----GSPPASPASALDRSLVAsckdSIGWMFSKLDTS-GDLFLDQAELA 73

                        90       100       110
                ....*....|....*....|....*....|....*..
gi 17541696 217 PITapVIPMESCIKPFLEGCDANNDGNISIKEWGKCL 253
Cdd:cd16238  74 AIN--LDKYEVCIRPFFNSCDTYRDGRVSTAEWCFCF 108

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 17541696 141 CTEEHMAQFPERMADWLfqvmkelkkrRELHkLEWEELLSEAENDDEKKH----VYPVI-----WKFCELDTKpHDKSVS 211
Cdd:cd16237   1 CTDKELRNLASRLKDWF----------GALH-EDANRVIKPTSSFTAQGRfdtsILPICkdslgWMFNKLDMN-YDLLLD 68

                        90       100       110       120
                ....*....|....*....|....*....|....*....|..
gi 17541696 212 HHELIPITapVIPMESCIKPFLEGCDANNDGNISIKEWGKCL 253
Cdd:cd16237  69 PSEISAIY--LDKYEPCMKPLFNSCDSFKDGKLSNNEWCYCF 108