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 634743251 390 CTDFEVIQFPLRMRDWLKNILMQLYEANSEHAGYLNEkqrnkvkkiyldekrllagdhpidlLLRDFKKNYHMYVYPVHW 469
Cdd:cd16231    1 CLDEELSEFPLRMRDWLKNVMVQLAERDELHEGLTEK-------------------------ELEDFQKNYKMYVYPVHW 55

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 634743251 470 QFSELDQHPMDRVLTHSELAPLRASLVPMEHCITRFFEECDPNKDKHITLKEWGHCFGIKE 530
Cdd:cd16231   56 KFCDLDQHPHDRYLSHHELAPLRAPLVPMEHCTTPFLETCDADNDKLISLKEWGACLGLKE 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 634743251 390 CTDFEVIQFPLRMRDWLKNILMQLYEANSEHAGYLNEkqrnkvkkiyldekrllagdhpidlLLRDFKKNYHMYVYPVHW 469
Cdd:cd16231    1 CLDEELSEFPLRMRDWLKNVMVQLAERDELHEGLTEK-------------------------ELEDFQKNYKMYVYPVHW 55

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 634743251 470 QFSELDQHPMDRVLTHSELAPLRASLVPMEHCITRFFEECDPNKDKHITLKEWGHCFGIKE 530
Cdd:cd16231   56 KFCDLDQHPHDRYLSHHELAPLRAPLVPMEHCTTPFLETCDADNDKLISLKEWGACLGLKE 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 634743251 308 CMSFQCKRGHICKADQQGKPHCVCQDPvtCPP-TKPLDQVCGTDNQTYASSCHLFATKCRLEGTKKGH------QLQLDY 380
Cdd:cd01328    2 CENHHCGAGKVCEVDDENTPKCVCIDP--CPEeVDDRRKVCTNDNETFDSDCELYRTRCLCKGGKKGCrgpkyqHLHLDY 79

                 ....*..
gi 634743251 381 FGACKSI 387
Cdd:cd01328   80 YGECKEI 86

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

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*
gi 634743251   330 VCqdPVTCPptKPLDQVCGTDNQTYASSCHLFATKCrlegtKKGHQLQLDYFGAC 384
Cdd:smart00280   1 DC--PEACP--REYDPVCGSDGVTYSNECHLCKAAC-----ESGKSIEVKHDGPC 46

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 634743251 390 CTDFEVIQFPLRMRDWLKNILMQLYEANSEHAGYLNEkqrnkvkkiyldekrllagdhpidlLLRDFKKNYHMYVYPVHW 469
Cdd:cd16231    1 CLDEELSEFPLRMRDWLKNVMVQLAERDELHEGLTEK-------------------------ELEDFQKNYKMYVYPVHW 55

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 634743251 470 QFSELDQHPMDRVLTHSELAPLRASLVPMEHCITRFFEECDPNKDKHITLKEWGHCFGIKE 530
Cdd:cd16231   56 KFCDLDQHPHDRYLSHHELAPLRAPLVPMEHCTTPFLETCDADNDKLISLKEWGACLGLKE 116

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 634743251  388 PTCTDFEVIQFPLRMRDWLKNILMQLYEANSEHagylnekqrnkvkkiyldekrllagDHPIDLLLRDFKKNYHMYVYPV 467
Cdd:pfam10591   1 PCCTDEELAEFPRRMRDWLKLLLEALRNRRERK-------------------------DHSSTLEKRDESLLYPCCKDPL 55

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 634743251  468 HWQFSELDQHpMDRVLTHSELAPLRASLVPMEHCITRFFEECDPNKDKHITLKEWGH 524
Cdd:pfam10591  56 GWMFKRLDTN-DDLLLDHEELAPIRAPLKPEEHCIKPFFESCDANKDKLISLEEWCC 111

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 634743251 308 CMSFQCKRGHICKADQQGKPHCVCQDPvtCPP-TKPLDQVCGTDNQTYASSCHLFATKCRLEGTKKGH------QLQLDY 380
Cdd:cd01328    2 CENHHCGAGKVCEVDDENTPKCVCIDP--CPEeVDDRRKVCTNDNETFDSDCELYRTRCLCKGGKKGCrgpkyqHLHLDY 79

                 ....*..
gi 634743251 381 FGACKSI 387
Cdd:cd01328   80 YGECKEI 86

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 634743251 390 CTDFEVIQFPLRMRDWLKNIlmqlyeanseHAgylNEKQRNKVKKiyldEKRLLAGDHPIdlllrdfkknyhmYVYPVHW 469
Cdd:cd16232    1 CTESELSEMGDRLLDWFSVL----------HE---QSNKAKKTSS----SKRFDKSHLPE-------------CKPSVGW 50

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 634743251 470 QFSELDQHpMDRVLTHSELAPLraSLVPMEHCITRFFEECDPNKDKHITLKEWGHCF 526
Cdd:cd16232   51 MFNQLDTN-NDLHLSQSELYDL--ELDKYEPCIKPFLDSCDRNKDGKISSDEWCDCF 104

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 634743251 467 VHWQFSELDQHPmDRVLTHSELAPLRA---SLVPMEHCITRFFEECDPNKDKHITLKEWGHCFGI 528
Cdd:cd16234   41 LDWKFSQLDKNK-NGVLERKEWKPFKRllkKAVKPKKCARKFPKYCDVNKDKKISLTEWLNCLGV 104

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

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*
gi 634743251   330 VCqdPVTCPptKPLDQVCGTDNQTYASSCHLFATKCrlegtKKGHQLQLDYFGAC 384
Cdd:smart00280   1 DC--PEACP--REYDPVCGSDGVTYSNECHLCKAAC-----ESGKSIEVKHDGPC 46

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 634743251 390 CTDFEVIQFPLRMRDWLKnilmQLYEANSEhagylnekqrNKVKKIYLDEKRLLAgDHPIDLLLRDfkknyhmyvyPVHW 469
Cdd:cd16239    1 CSDLEFREVANRLRDWFK----ALHESGSQ----------NKKTKIVRRPERSRF-DTSILPICKD----------SLGW 55

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 634743251 470 QFSELDQHpMDRVLTHSELAPLRasLVPMEHCITRFFEECDPNKDKHITLKEWGHCF 526
Cdd:cd16239   56 MFNRLDTN-YDLLLDQSELGSIY--LDKNEQCTKAFFNSCDTYKDSLISNNEWCYCF 109

EF-hand, extracellular calcium-binding (EC) motif, found in secreted modular calcium-binding protein 1 (SMOC-1); SMOC-1, also termed SPARC-related modular calcium-binding protein 1, or smooth muscle-associated protein 1 (SMAP-1), is an Arf6 GTPase-activating protein (GAP) that directly interacts with clathrin and regulates the clathrin-dependent endocytosis of transferrin receptors from the plasma membrane. It is predominantly localized in basement membranes. SMOC-1 acts as a regulator of osteoblast differentiation and is involved in inhibition of transforming growth factor-beta (TGF-beta) signaling through production of nitric oxide. It also plays an essential role in ocular and limb development and functions as a regulator of bone morphogenic protein (BMP) signaling. It interacts with a matricellular protein, tenascin C in addition to the serum proteins, fibulin-1 and C-reactive protein, but not collagens. Two point mutations in the SMOC1 gene may cause Waardenburg Anophtalmia Syndrome. Moreover, SMOC-1 is involved in direct or indirect modulation of growth factor signaling pathways and plays a role in physiological processes involving extensive tissue remodeling. SMOC-1 contains a follistatin-like (FS) domain, two thyroglobulin-like (TY) domains, a novel domain, which is found only in the homologous SMOC-2, and an extracellular calcium-binding (EC) domain with two EF-hand calcium-binding motifs.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 634743251 467 VHWQFSELDQHPMDRVlTHSELAPLRASL---VPMEHCITRFFEECDPNKDKHITLKEWGHCFGIKE 530
Cdd:cd16240   50 VHWYFSQLDNNSSNDI-NKKELKPFKRYVkkkAKPKKCARRFTDYCDLNKDKSISLQELKGCLGVSK 115

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 634743251 467 VHWQFSELDQHPmDRVLTHSELAPLraSLVPMEHCITRFFEECDPNKDKHITLKEWGHCF 526
Cdd:cd16238   52 IGWMFSKLDTSG-DLFLDQAELAAI--NLDKYEVCIRPFFNSCDTYRDGRVSTAEWCFCF 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
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 634743251 469 WQFSELDQHpMDRVLTHSELAPLraSLVPMEHCITRFFEECDPNKDKHITLKEWGHCF 526
Cdd:cd16237   54 WMFNKLDMN-YDLLLDPSEISAI--YLDKYEPCMKPLFNSCDSFKDGKLSNNEWCYCF 108