EF-hand, extracellular calcium-binding (EC) motif, found in follistatin-related protein 1 (FRP-1); FRP-1, also termed follistatin-like protein 1 (fstl-1), TGF-beta-stimulated clone 36 (TSC-36/Flik), or TGF-beta inducible protein, is a secreted glycoprotein that is overexpressed in certain inflammatory diseases and has been implicated in many autoimmune diseases. FRP-1 functions as an important proinflammatory factor in the pathogenesis of osteoarthritis (OA) by activating the canonical NF-kappaB-mediated inflammatory cytokines, including tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta) and interleukin-6 (IL-6), and enhancing fibroblast like synoviocytes proliferation. It also acts as a critical mediator of collagen-induced arthritis (CIA), juvenile rheumatoid arthritis (JRA), as well as Lyme arthritis observed after Borrelia burgdorferi infection. Meanwhile, it enhances nod-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome-mediated IL-1beta secretion from monocytes and macrophages. Moreover, FRP-1 shows critical functions in the nervous system. It differentially regulates transforming growth factor beta (TGF-beta) and bone morphogenetic protein (BMP) signaling, leading to epithelial injury and fibroblast activation. Furthermore, FRP-1 functions as a cardiokine with cardioprotective properties. It may play a potential role in ischemic stroke through decreasing neuronal apoptosis and improving neurological deficits via disco-interacting protein 2 homolog A (DIP2A)/Akt pathway after middle cerebral artery occlusion (MCAO). Plasma FRP-1 is elevated in Kawasaki disease (KD) and thus may play a possible role in the formation of coronary artery aneurysm (CAA). FRP-1 contains a follistatin-like (FS) domain, an extracellular calcium-binding (EC) domain including a pair of EF hands, and a von Willebrand factor type C (VWC) domain. The EC domain does not undergo characteristic structural changes upon calcium addition or depletion and therefore is not a functional calcium binding domain.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 432114613 128 CYQSNRDELRRRIIQWLEAEIIPDGWFSKGSNYSEILDKYFKNFDNGDSRLDSSEFLKFVEQNETAINITTYADQENNKL 207
Cdd:cd16233    1 CYQSDRDELRRRVIDWLQTEVIPDGWFTKGSSYSDILDKYFKKYDNGDSQLDSNELLKFVEQNETATNLTLYQDEETNKL 80

                         90       100       110
                 ....*....|....*....|....*....|....
gi 432114613 208 LRGLCVDALIELSDENADWKLSFQEFLKCLNPSF 241
Cdd:cd16233   81 LRGLCVDALIELSDENADWKLNFEEFLKCLNPSF 114

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

                           10        20
                   ....*....|....*....|...
gi 432114613    46 CANVFCGAGRECAVTEKGEPTCL 68
Cdd:smart00274   2 CRNVQCPFGKVCVVDKNGNARCV 24

EF-hand, extracellular calcium-binding (EC) motif, found in follistatin-related protein 1 (FRP-1); FRP-1, also termed follistatin-like protein 1 (fstl-1), TGF-beta-stimulated clone 36 (TSC-36/Flik), or TGF-beta inducible protein, is a secreted glycoprotein that is overexpressed in certain inflammatory diseases and has been implicated in many autoimmune diseases. FRP-1 functions as an important proinflammatory factor in the pathogenesis of osteoarthritis (OA) by activating the canonical NF-kappaB-mediated inflammatory cytokines, including tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta) and interleukin-6 (IL-6), and enhancing fibroblast like synoviocytes proliferation. It also acts as a critical mediator of collagen-induced arthritis (CIA), juvenile rheumatoid arthritis (JRA), as well as Lyme arthritis observed after Borrelia burgdorferi infection. Meanwhile, it enhances nod-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome-mediated IL-1beta secretion from monocytes and macrophages. Moreover, FRP-1 shows critical functions in the nervous system. It differentially regulates transforming growth factor beta (TGF-beta) and bone morphogenetic protein (BMP) signaling, leading to epithelial injury and fibroblast activation. Furthermore, FRP-1 functions as a cardiokine with cardioprotective properties. It may play a potential role in ischemic stroke through decreasing neuronal apoptosis and improving neurological deficits via disco-interacting protein 2 homolog A (DIP2A)/Akt pathway after middle cerebral artery occlusion (MCAO). Plasma FRP-1 is elevated in Kawasaki disease (KD) and thus may play a possible role in the formation of coronary artery aneurysm (CAA). FRP-1 contains a follistatin-like (FS) domain, an extracellular calcium-binding (EC) domain including a pair of EF hands, and a von Willebrand factor type C (VWC) domain. The EC domain does not undergo characteristic structural changes upon calcium addition or depletion and therefore is not a functional calcium binding domain.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 432114613 128 CYQSNRDELRRRIIQWLEAEIIPDGWFSKGSNYSEILDKYFKNFDNGDSRLDSSEFLKFVEQNETAINITTYADQENNKL 207
Cdd:cd16233    1 CYQSDRDELRRRVIDWLQTEVIPDGWFTKGSSYSDILDKYFKKYDNGDSQLDSNELLKFVEQNETATNLTLYQDEETNKL 80

                         90       100       110
                 ....*....|....*....|....*....|....
gi 432114613 208 LRGLCVDALIELSDENADWKLSFQEFLKCLNPSF 241
Cdd:cd16233   81 LRGLCVDALIELSDENADWKLNFEEFLKCLNPSF 114

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 432114613  73 CKPHKRPVCGSNGKTYLNHCELHRDACLTGSKIQVDYDGHC 113
Cdd:cd00104    1 CPKEYDPVCGSDGKTYSNECHLGCAACRSGRSITVAHNGPC 41

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 432114613  168 FKNFD-NGDSRLDSSEFLKFVEQNETAINITtyaDQEnnkllrglcVDALIELSDENADWKLSFQEFLK 235
Cdd:pfam13499   8 FKLLDsDGDGYLDVEELKKLLRKLEEGEPLS---DEE---------VEELFKEFDLDKDGRISFEEFLE 64

von Willebrand factor (vWF) type C domain;

                           10        20        30
                   ....*....|....*....|....*....|....*....
gi 432114613   248 CALEDEMYADGAETEVDCNRCVCACGNWVCTAMTCDGKN 286
Cdd:smart00215   1 CWNNGSYYPPGAKWDDDCNRCTCLNGRVSCTKVWCGPKP 39

EF-hand, extracellular calcium-binding (EC) motif, found in follistatin-related protein 1 (FRP-1); FRP-1, also termed follistatin-like protein 1 (fstl-1), TGF-beta-stimulated clone 36 (TSC-36/Flik), or TGF-beta inducible protein, is a secreted glycoprotein that is overexpressed in certain inflammatory diseases and has been implicated in many autoimmune diseases. FRP-1 functions as an important proinflammatory factor in the pathogenesis of osteoarthritis (OA) by activating the canonical NF-kappaB-mediated inflammatory cytokines, including tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta) and interleukin-6 (IL-6), and enhancing fibroblast like synoviocytes proliferation. It also acts as a critical mediator of collagen-induced arthritis (CIA), juvenile rheumatoid arthritis (JRA), as well as Lyme arthritis observed after Borrelia burgdorferi infection. Meanwhile, it enhances nod-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome-mediated IL-1beta secretion from monocytes and macrophages. Moreover, FRP-1 shows critical functions in the nervous system. It differentially regulates transforming growth factor beta (TGF-beta) and bone morphogenetic protein (BMP) signaling, leading to epithelial injury and fibroblast activation. Furthermore, FRP-1 functions as a cardiokine with cardioprotective properties. It may play a potential role in ischemic stroke through decreasing neuronal apoptosis and improving neurological deficits via disco-interacting protein 2 homolog A (DIP2A)/Akt pathway after middle cerebral artery occlusion (MCAO). Plasma FRP-1 is elevated in Kawasaki disease (KD) and thus may play a possible role in the formation of coronary artery aneurysm (CAA). FRP-1 contains a follistatin-like (FS) domain, an extracellular calcium-binding (EC) domain including a pair of EF hands, and a von Willebrand factor type C (VWC) domain. The EC domain does not undergo characteristic structural changes upon calcium addition or depletion and therefore is not a functional calcium binding domain.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 432114613 128 CYQSNRDELRRRIIQWLEAEIIPDGWFSKGSNYSEILDKYFKNFDNGDSRLDSSEFLKFVEQNETAINITTYADQENNKL 207
Cdd:cd16233    1 CYQSDRDELRRRVIDWLQTEVIPDGWFTKGSSYSDILDKYFKKYDNGDSQLDSNELLKFVEQNETATNLTLYQDEETNKL 80

                         90       100       110
                 ....*....|....*....|....*....|....
gi 432114613 208 LRGLCVDALIELSDENADWKLSFQEFLKCLNPSF 241
Cdd:cd16233   81 LRGLCVDALIELSDENADWKLNFEEFLKCLNPSF 114

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

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*
gi 432114613    69 CIEQCKPHKRPVCGSNGKTYLNHCELHRDACLTGSKIQVDYDGHC 113
Cdd:smart00280   2 CPEACPREYDPVCGSDGVTYSNECHLCKAACESGKSIEVKHDGPC 46

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 432114613  46 CANVFCGAGRECAVTEKGEPTCLCIEQCKPH---KRPVCGSNGKTYLNHCELHRDACL-----------TGSKIQVDYDG 111
Cdd:cd01328    2 CENHHCGAGKVCEVDDENTPKCVCIDPCPEEvddRRKVCTNDNETFDSDCELYRTRCLckggkkgcrgpKYQHLHLDYYG 81

                 ....
gi 432114613 112 HCKE 115
Cdd:cd01328   82 ECKE 85

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 432114613  168 FKNFD-NGDSRLDSSEFLKFVEQNETAINITtyaDQEnnkllrglcVDALIELSDENADWKLSFQEFLK 235
Cdd:pfam13499   8 FKLLDsDGDGYLDVEELKKLLRKLEEGEPLS---DEE---------VEELFKEFDLDKDGRISFEEFLE 64

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        30        40
                 ....*....|....*....|....*....|....*....|.
gi 432114613  73 CKPHKRPVCGSNGKTYLNHCELHRDACLTGSKIQVDYDGHC 113
Cdd:cd01327    5 CPKDYDPVCGTDGVTYSNECLLCAENLKRQTNIRIKHDGEC 45

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        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 432114613 164 LDKYFKNFD-NGDSRLDSSEFLKFVEQNETainitTYADQEnnkllrglcVDALIELSDENADWKLSFQEFLK 235
Cdd:cd00051    2 LREAFRLFDkDGDGTISADELKAALKSLGE-----GLSEEE---------IDEMIREVDKDGDGKIDFEEFLE 60

EF-hand, calcium binding motif, found in reticulocalbin-2 (RCN2) mainly from protostomes; This family corresponds to a group of uncharacterized RCN2-like proteins, which are mainly found in protostomes. Although their biological function remains unclear, they show high sequence similarity with RCN2 (also known as E6BP or TCBP-49), which is an endoplasmic reticulum resident low-affinity Ca2+-binding protein that has been implicated in immunity, redox homeostasis, cell cycle regulation and coagulation. Members in this family contain six copies of the EF-hand Ca2+-binding motif, but may lack a C-terminal His-Asp-Glu-Leu (HDEL) tetrapeptide that is required for retention of RCN2 in the endoplasmic reticulum (ER).

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 432114613 165 DKYFKNFD-NGDSRLDSSEFLKFVEQNETAInittyADQEnnkllrglcVDALIELSDENADWKLSFQEFL 234
Cdd:cd16227  199 DRFDEDYDkDGDGKLDGEEILSWLVPDNEEI-----AEEE---------VDHLFASADDDHDDRLSFDEIL 255