PROSITE documentation PDOC00966 [for PROSITE entry PS01254]
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 <PDOC00259>) 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 α-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 β-sheet wrapped around a five-turn α-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.

Last update:

March 2011 / Text revised; profiles added.


Technical section

PROSITE methods (with tools and information) covered by this documentation:

FETUIN_1, PS01254; Fetuin family signature 1  (PATTERN)

CYSTATIN_FETUIN_A, PS51529; Fetuin-A-type cystatin domain profile  (MATRIX)

CYSTATIN_FETUIN_B, PS51530; Fetuin-B-type cystatin domain profile  (MATRIX)

FETUIN_2, PS01255; Fetuin family signature 2  (PATTERN)


1AuthorsKordis D. Turk V.
TitlePhylogenomic analysis of the cystatin superfamily in eukaryotes and prokaryotes.
SourceBMC Evol. Biol. 9:266-266(2009).
PubMed ID19919722

2AuthorsBrown W.M. Dziegielewska K.M. Saunders N.R. Christie D.L. Nawratil P. Mueller-Esterl W.
TitleThe nucleotide and deduced amino acid structures of sheep and pig fetuin. Common structural features of the mammalian fetuin family.
SourceEur. J. Biochem. 205:321-331(1992).
PubMed ID1372866

3AuthorsYang F. Chen Z.-L. Bergeron J.M. Cupples R.L. Friedrichs W.E.
TitleHuman alpha 2-HS-glycoprotein/bovine fetuin homologue in mice: identification and developmental regulation of the gene.
SourceBiochim. Biophys. Acta 1130:149-156(1992).
PubMed ID1373325

4AuthorsHaasemann M. Nawratil P. Mueller-Esterl W.
TitleRat tyrosine kinase inhibitor shows sequence similarity to human alpha 2-HS glycoprotein and bovine fetuin.
SourceBiochem. J. 274:899-902(1991).
PubMed ID1707273

5AuthorsGoto K. Yoshida K. Suzuki Y. Yamamoto K. Sinohara H.
TitleMolecular cloning and sequencing of cDNA encoding plasma countertrypin, a member of mammalian fetuin family, from the Mongolian gerbil, Meriones unguiculatus.
SourceJ. Biochem. 121:619-625(1997).
PubMed ID9133634

6AuthorsHeiss A. DuChesne A. Denecke B. Groetzinger J. Yamamoto K. Renne T. Jahnen-Dechent W.
TitleStructural basis of calcification inhibition by alpha 2-HS glycoprotein/fetuin-A. Formation of colloidal calciprotein particles.
SourceJ. Biol. Chem. 278:13333-13341(2003).
PubMed ID12556469

7AuthorsAoki N. Deshimaru M. Kihara K. Terada S.
TitleSnake fetuin: isolation and structural analysis of new fetuin family proteins from the sera of venomous snakes.
SourceToxicon 54:481-490(2009).
PubMed ID19481564

8AuthorsOlivier E. Soury E. Ruminy P. Husson A. Parmentier F. Daveau M.
TitleSalier J.-P. Fetuin-B, a second member of the fetuin family in mammals.
SourceBiochem. J. 350:589-597(2000).
PubMed ID10947975

9AuthorsLiu J.-X. Zhai Y.-H. Geng F.-S. Xia J.-H. Gui J.-F.
TitleMolecular characterization and expression pattern of fetuin-B in gibel carp (Carassius auratus gibelio).
SourceBiochem. Genet. 46:620-633(2008).
PubMed ID18751887

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