{PDOC00966} {PS01254; FETUIN_1} {PS01255; FETUIN_2} {PS51529; CYSTATIN_FETUIN_A} {PS51530; CYSTATIN_FETUIN_B} {BEGIN} ************************************************************************************* * Fetuin family signatures and fetuin-A- and fetuin-B-type cystatin domain profiles * ************************************************************************************* The cystatin superfamily consists of a large group of cystatin domain- containing proteins, most of which are reversible and tight-binding inhibitors of the papain (C1) and legumain (C13) families of cysteine proteases. Fetuins have been identified as main members of the cystatin superfamily and are composed of fetuin-A and fetuin-B. Fetuins are characterized by the presence of 2 N-terminally located cystatin-like repeats (see ) and a unique C-terminal domain which is not present in other proteins of the cystatin family [1,2,3]. Fetuin-A [2,3,4,5,6] also called alpha-2-HS-glycoprotein, bone sialic acid- containing protein (BSP), countertrypin or PP63, is expressed in a tissue- and development-specific pattern which seems to be significantly different between species. A wide functional diversity of fetuin-A has been observed. It has been shown to function in many physiological aspects, such as fatty acid transport, regulation of insulin activity and hepatocyte-growth-factor activity, response to systemic inflammation, and inhibition of unwanted mineralization. It has been demonstrated that fetuin-A plays important roles during developmental processes, including osteogenesis, myotubule, fetal brain and nervous system development. Human fetuin is a heterodimer of chain A and B, which are derived by cleavage of a connecting peptide from a common precursor. Snake fetuin family proteins (antihemorrhagic proteins HSF, BJ46a and MSF and HLP-A and HLP-B) show a significant degree of sequence homology to fetuin-A [7]. Fetuin-B has been suggested to be involved in systemic inflammation, as a tumor suppressor, and as a basic calcium phosphate precipitation inhibitor [8,9]. The cystatin fold is formed by a five stranded anti-parallel beta-sheet wrapped around a five-turn alpha-helix [1]. As shown in the schematic representation fetuin contains twelve conserved cysteines involved in six disulfide bonds. Chain A Chain B +--+ +---+ +-+ +--+ +---+ **********|**|**|***|**|*| | | | | xCxxxxxxxxxCxxCxxCxxxCxxCxCxxxxxxxxxCxxCxxCxxxCxxxxxxxxx xxxxxxxxCxx | *** | +----------------------------------------------------------------+ 'C': conserved cysteine involved in a disulfide bond. '*': position of pattern 1 (upper line) and 2 (lower line). Eleven of the twelve invariant cysteines are located within the cystatin-like repeats. This domain has been choosen to assign a signature pattern. The 12th cysteine is located near the C-terminus of the protein, separated by a region of variable length. A second signature pattern has been developed from a well conserved region around the 2nd invariant cysteine. We also developped two profiles, which cover respectively the fetuin-A- and fetuin-B-type cystatin domains. -Consensus pattern: C-[DN]-[DE]-x(54)-C-H-x(9)-C-x(12,14)-C-x(17,19)-C-x(13)- C-x(2)-C [The 7 C's are involved in a disulfide bond] -Sequences known to belong to this class detected by the pattern: ALL. -Other sequence(s) detected in Swiss-Prot: NONE. -Consensus pattern: [ND]-x-L-E-T-x-C-H-x-L [C is involved in a disulfide bond] -Sequences known to belong to this class detected by the pattern: ALL. -Other sequence(s) detected in Swiss-Prot: NONE. -Sequences known to belong to this class detected by the profile: ALL. -Other sequence(s) detected in Swiss-Prot: NONE. -Sequences known to belong to this class detected by the profile: ALL. -Other sequence(s) detected in Swiss-Prot: NONE. -Last update: March 2011 / Text revised; profiles added. [ 1] Kordis D., Turk V. "Phylogenomic analysis of the cystatin superfamily in eukaryotes and prokaryotes." BMC Evol. Biol. 9:266-266(2009). PubMed=19919722; DOI=10.1186/1471-2148-9-266 [ 2] Brown W.M., Dziegielewska K.M., Saunders N.R., Christie D.L., Nawratil P., Mueller-Esterl W. "The nucleotide and deduced amino acid structures of sheep and pig fetuin. Common structural features of the mammalian fetuin family." Eur. J. Biochem. 205:321-331(1992). PubMed=1372866 [ 3] Yang F., Chen Z.-L., Bergeron J.M., Cupples R.L., Friedrichs W.E. "Human alpha 2-HS-glycoprotein/bovine fetuin homologue in mice: identification and developmental regulation of the gene." Biochim. Biophys. Acta 1130:149-156(1992). PubMed=1373325 [ 4] Haasemann M., Nawratil P., Mueller-Esterl W. "Rat tyrosine kinase inhibitor shows sequence similarity to human alpha 2-HS glycoprotein and bovine fetuin." Biochem. J. 274:899-902(1991). PubMed=1707273 [ 5] Goto K., Yoshida K., Suzuki Y., Yamamoto K., Sinohara H. "Molecular cloning and sequencing of cDNA encoding plasma countertrypin, a member of mammalian fetuin family, from the Mongolian gerbil, Meriones unguiculatus." J. Biochem. 121:619-625(1997). PubMed=9133634 [ 6] Heiss A., DuChesne A., Denecke B., Groetzinger J., Yamamoto K., Renne T., Jahnen-Dechent W. "Structural basis of calcification inhibition by alpha 2-HS glycoprotein/fetuin-A. Formation of colloidal calciprotein particles." J. Biol. Chem. 278:13333-13341(2003). PubMed=12556469; DOI=10.1074/jbc.M210868200 [ 7] Aoki N., Deshimaru M., Kihara K., Terada S. "Snake fetuin: isolation and structural analysis of new fetuin family proteins from the sera of venomous snakes." Toxicon 54:481-490(2009). PubMed=19481564; DOI=10.1016/j.toxicon.2009.05.018 [ 8] Olivier E., Soury E., Ruminy P., Husson A., Parmentier F., Daveau M., Salier J.-P. "Fetuin-B, a second member of the fetuin family in mammals." Biochem. J. 350:589-597(2000). PubMed=10947975 [ 9] Liu J.-X., Zhai Y.-H., Geng F.-S., Xia J.-H., Gui J.-F. "Molecular characterization and expression pattern of fetuin-B in gibel carp (Carassius auratus gibelio)." Biochem. Genet. 46:620-633(2008). PubMed=18751887; DOI=10.1007/s10528-008-9176-4 -------------------------------------------------------------------------------- PROSITE is copyrighted by the SIB Swiss Institute of Bioinformatics and distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND 4.0) License, see https://prosite.expasy.org/prosite_license.html -------------------------------------------------------------------------------- {END}