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 1937369345 485 CTDFEVAQFPLRMRDWLKNILMQLYepnpkhggylnekqrskvkkiyldekrllagdhpielllrdfkknyhmYVYPVHW 564
Cdd:cd16236     1 CTDSEVVQFPLRMRDWLKNILMQLY------------------------------------------------YIYPVHW 32

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1937369345 565 QFNELDQHPADRILTHSELAPLRASLVPMEHCITRFFEECDPNKDKHITLKEWGHCFGIKE 625
Cdd:cd16236    33 QFAQLDQHPSDRFLTHSELAPLRASLVPMEHCITRFFQECDADKDKLITLKEWCHCFGIKE 93

MSCRAMM family adhesin clumping factor ClfA; Clumping factor A is an MSCRAMM (Microbial Surface Components Recognizing Adhesive Matrix Molecules). It is heavily studied in Staphylococcus aureus both for its biological role in adhesion and for its potential for vaccination. Features of the sequence, but also of other MSCRAMM adhesins, include a long run of Ser-Asp dipeptide repeats and a C-terminal cell wall anchoring LPXTG motif.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1937369345  46 AEAAADIEKHPNDKAEKPSALNSEEEAHEQS-TEQDKTYSFEVDLKDEEDGDGDLSVDPTERTLDLQEGTSEPQQKRLPE 124
Cdd:NF033609  660 SDSDSDSDSDSDSDSDSDSDSDSDSDSDSDSdSDSDSDSDSDSDSDSDSDSDSDSDSDSDSDSDSDSDSDSDSDSDSDSD 739

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1937369345 125 NAGFPATVSTPFVDSDQPANITKGEESQEQPVSDSHQQQDESGKQTQDSMTEESHKQDPGIPNEEKEEEEDPEDVGAPSD 204
Cdd:NF033609  740 SDSDSDSDSDSDSDSDSDSDSDSDSDSDSDSDSDSDSDSDSDSDSDSDSDSDSDSDSDSDSDSDSDSDSDSDSDSDSDSD 819

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1937369345 205 NQEEEKEPPEEQPTSKWEGNGDQSEDILQES-SQPTQISKTKNDFEQGSQGQ-------EGDSNAEGEDKAAGSKEHLPH 276
Cdd:NF033609  820 SDSDSDSDSDSDSDSDSDSDSDSDSDSDSDSdSDSDSESDSNSDSESGSNNNvvppnspKNGTNASNKNEAKDSKEPLPD 899

                         250
                  ....*....|....*
gi 1937369345 277 TewqGQEGRAGLDAI 291
Cdd:NF033609  900 T---GSEDEANTSLI 911

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 1937369345 485 CTDFEVAQFPLRMRDWLKNILMQLYepnpkhggylnekqrskvkkiyldekrllagdhpielllrdfkknyhmYVYPVHW 564
Cdd:cd16236     1 CTDSEVVQFPLRMRDWLKNILMQLY------------------------------------------------YIYPVHW 32

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1937369345 565 QFNELDQHPADRILTHSELAPLRASLVPMEHCITRFFEECDPNKDKHITLKEWGHCFGIKE 625
Cdd:cd16236    33 QFAQLDQHPSDRFLTHSELAPLRASLVPMEHCITRFFQECDADKDKLITLKEWCHCFGIKE 93

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 1937369345 403 CMNFQCKRGHTCKTDQHGKPHCVCQDPetCPPA-KILDQACGTDNQTYASSCHLFATKCMLEGTKKGH------QLQLDY 475
Cdd:cd01328     2 CENHHCGAGKVCEVDDENTPKCVCIDP--CPEEvDDRRKVCTNDNETFDSDCELYRTRCLCKGGKKGCrgpkyqHLHLDY 79

                  ....*..
gi 1937369345 476 FGACKSI 482
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 1937369345  425 VCqdPETCPpaKILDQACGTDNQTYASSCHLFATKCmlegtKKGHQLQLDYFGAC 479
Cdd:smart00280   1 DC--PEACP--REYDPVCGSDGVTYSNECHLCKAAC-----ESGKSIEVKHDGPC 46

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 1937369345 485 CTDFEVAQFPLRMRDWLKNILMQLYepnpkhggylnekqrskvkkiyldekrllagdhpielllrdfkknyhmYVYPVHW 564
Cdd:cd16236     1 CTDSEVVQFPLRMRDWLKNILMQLY------------------------------------------------YIYPVHW 32

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1937369345 565 QFNELDQHPADRILTHSELAPLRASLVPMEHCITRFFEECDPNKDKHITLKEWGHCFGIKE 625
Cdd:cd16236    33 QFAQLDQHPSDRFLTHSELAPLRASLVPMEHCITRFFQECDADKDKLITLKEWCHCFGIKE 93

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 1937369345 483 PACTDFEVAQFPLRMRDWLKNILMQLYEPNPKHggylnekqrskvkkiyldekrllagDHPIELLLRDFKKNYHMYVYPV 562
Cdd:pfam10591   1 PCCTDEELAEFPRRMRDWLKLLLEALRNRRERK-------------------------DHSSTLEKRDESLLYPCCKDPL 55

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 1937369345 563 HWQFNELDQHpADRILTHSELAPLRASLVPMEHCITRFFEECDPNKDKHITLKEWGH 619
Cdd:pfam10591  56 GWMFKRLDTN-DDLLLDHEELAPIRAPLKPEEHCIKPFFESCDANKDKLISLEEWCC 111

EF-hand, extracellular calcium-binding (EC) motif, found in secreted protein acidic and rich in cysteine (SPARC)-like proteins; The SPARC protein family represents a diverse group of proteins that share a follistatin-like (FS) domain and an extracellular calcium-binding (EC) domain with two EF-hand motifs. It includes SPARC (for secreted protein acidic and rich in cysteine, also termed osteonectin/ON, or basement-membrane protein 40/BM-40), SPARC-like protein 1 (for secreted protein, acidic and rich in cysteines-like 1/ SPARCL1, also termed high endothelial venule protein/Hevi, or MAST 9, or SC-1, or RAGS-1, or QR1, or ECM 2), testicans 1, 2, and 3 (also termed SPARC/osteonectin, CWCV, and Kazal-like domains proteoglycans, or SPOCK), secreted modular calcium-binding protein SMOC-1 (also termed SPARC-related modular calcium-binding protein 1) and SMOC-2 (also termed SPARC-related modular calcium-binding protein 2, or smooth muscle-associated protein 2/SMAP-2), follistatin-related protein 1 (FRP-1, also termed follistatin-like protein 1/fstl-1, TSC-36/Flik, TGF-beta inducible protein). The SPARC proteins have been implicated in modulating cell interaction with the extracellular milieu, including regulation of extracellular matrix assembly and deposition, counter-adhesion, effects on extracellular protease activity, and modulation of growth factor/cytokine signaling pathways, as well as in development and disease.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1937369345 485 CTDFEVAQFPLRMRDWLKNILMQLYEPNPkhggylnekqrskvkkiyldekrllagdhpiELLLRDFKKNYHMYVYPVHW 564
Cdd:cd00252     1 CPGSELMQFPDRLLDWLLLLKEQDENRSY-------------------------------DNNKRGHDLSGTMRKEIAQW 49

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 1937369345 565 QFNELDQhPADRILTHSELAPLRASLVPMEHCITRFFEECDPNKDKHITLKEWGHCFGI 623
Cdd:cd00252    50 EFDNLDN-NKDGKLDKRELAPFRAPLMPLEHCARGFFESCDLNKDKKISLQEWLGCFGV 107

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 1937369345 485 CTDFEVAQFPLRMRDWLKNILMQlyepnpkhgGYLNEKQRSKvkkiyldeKRLLAGDHPIellLRDfkknyhmyvyPVHW 564
Cdd:cd16232     1 CTESELSEMGDRLLDWFSVLHEQ---------SNKAKKTSSS--------KRFDKSHLPE---CKP----------SVGW 50

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 1937369345 565 QFNELDQHpADRILTHSELAPLraSLVPMEHCITRFFEECDPNKDKHITLKEWGHCF 621
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 1937369345 562 VHWQFNELDQHpADRILTHSELAPLRA---SLVPMEHCITRFFEECDPNKDKHITLKEWGHCFGI 623
Cdd:cd16234    41 LDWKFSQLDKN-KNGVLERKEWKPFKRllkKAVKPKKCARKFPKYCDVNKDKKISLTEWLNCLGV 104

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 1937369345 485 CTDFEVAQFPLRMRDWLKnilmQLYEpnpkhggylNEKQRSKVKKIYLDEKRLLagDHPIELLLRDfkknyhmyvyPVHW 564
Cdd:cd16239     1 CSDLEFREVANRLRDWFK----ALHE---------SGSQNKKTKIVRRPERSRF--DTSILPICKD----------SLGW 55

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 1937369345 565 QFNELDQHpADRILTHSELAPLraSLVPMEHCITRFFEECDPNKDKHITLKEWGHCF 621
Cdd:cd16239    56 MFNRLDTN-YDLLLDQSELGSI--YLDKNEQCTKAFFNSCDTYKDSLISNNEWCYCF 109

Follistatin/Osteonectin-like EGF domain; Members of this family are predominantly found in osteonectin and follistatin and adopt an EGF-like fold.

                          10        20
                  ....*....|....*....|..
gi 1937369345 403 CMNFQCKRGHTCKTDQHGKPHC 424
Cdd:pfam09289   1 CENFQCKRGKVCKVDKEGKPHC 22

EF-hand, extracellular calcium-binding (EC) motif, found in secreted modular calcium-binding protein 2 (SMOC-2); SMOC-2, also termed SPARC-related modular calcium-binding protein 2, or smooth muscle-associated protein 2 (SMAP-2), is a ubiquitously expressed matricellular protein that enhances the response to angiogenic growth factors, mediate cell adhesion, keratinocyte migration, and metastasis. It is also associated with vitiligo and craniofacial and dental defects. Moreover, SMOC-2 acts as an Arf1 GTPase-activating protein (GAP) that interacts with clathrin heavy chain (CHC) and clathrin assembly protein CALM and functions in the retrograde, early endosome/trans-Golgi network (TGN) pathway in a clathrin- and AP-1-dependent manner. It also contributes to mitogenesis via activation of integrin-linked kinase (ILK). SMOC-2 contains a follistatin-like (FS) domain, two thyroglobulin-like (TY) domains, a novel domain, which is found only in the homologous SMOC-1, and an extracellular calcium-binding (EC) domain with two EF-hand calcium-binding motifs.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1937369345 562 VHWQFNELDQHPADRIlTHSELAP----LRASLVPmEHCITRFFEECDPNKDKHITLKEWGHCFGI 623
Cdd:cd16241    49 VHWYFKQLDKNSSGDI-GKKEIKPfkrfLRKKSKP-KKCVKKFVEYCDVNNDKSLSVQELMGCLGV 112

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 1937369345 432 CPpaKILDQACGTDNQTYASSCHLFATKCmlegtKKGHQLQLDYFGAC 479
Cdd:cd00104     1 CP--KEYDPVCGSDGKTYSNECHLGCAAC-----RSGRSITVAHNGPC 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
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 1937369345 564 WQFNELDQHpADRILTHSELAPLRasLVPMEHCITRFFEECDPNKDKHITLKEWGHCF 621
Cdd:cd16237    54 WMFNKLDMN-YDLLLDPSEISAIY--LDKYEPCMKPLFNSCDSFKDGKLSNNEWCYCF 108

Kazal-type pancreatic secretory trypsin inhibitors (PSTI) and related proteins, including the second domain of the ovomucoid turkey inhibitor and the C-terminal domain of the esophagus cancer-related gene-2 protein (ECRG-2), are members of the superfamily of kazal-type proteinase inhibitors and follistatin-like proteins.

                          10        20
                  ....*....|....*....|....
gi 1937369345 432 CPpaKILDQACGTDNQTYASSCHL 455
Cdd:cd01327     5 CP--KDYDPVCGTDGVTYSNECLL 26