PROSITE documentation PDOC00966

Fetuin family signatures and fetuin-A- and fetuin-B-type cystatin domain profiles

Description

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:

CYSTATIN_FETUIN_A, PS51529; Fetuin-A-type cystatin domain profile  (MATRIX)
Sequences known to belong to this class detected by the profile: ALL
Other sequence(s) detected in Swiss-Prot: NONE.
• Domain architecture view of Swiss-Prot proteins matching PS51529
PS51529
• Retrieve an alignment of Swiss-Prot true positive hits:
  Clustal format, color, condensed view  / Clustal format, color  / Clustal format, plain text  / Fasta format
• Retrieve the sequence logo from the alignment
• Taxonomic tree view of all Swiss-Prot/TrEMBL entries matching PS51529
• Retrieve a list of all Swiss-Prot/TrEMBL entries matching PS51529
• Scan Swiss-Prot/TrEMBL entries against PS51529
• view ligand binding statistics
CYSTATIN_FETUIN_B, PS51530; Fetuin-B-type cystatin domain profile  (MATRIX)
Sequences known to belong to this class detected by the profile: ALL
Other sequence(s) detected in Swiss-Prot: NONE.
• Domain architecture view of Swiss-Prot proteins matching PS51530
PS51530
• Retrieve an alignment of Swiss-Prot true positive hits:
  Clustal format, color, condensed view  / Clustal format, color  / Clustal format, plain text  / Fasta format
• Retrieve the sequence logo from the alignment
• Taxonomic tree view of all Swiss-Prot/TrEMBL entries matching PS51530
• Retrieve a list of all Swiss-Prot/TrEMBL entries matching PS51530
• Scan Swiss-Prot/TrEMBL entries against PS51530
• view ligand binding statistics
FETUIN_1, PS01254; Fetuin family signature 1  (PATTERN)
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.
• Retrieve an alignment of Swiss-Prot true positive hits:
  Clustal format, color, condensed view  / Clustal format, color  / Clustal format, plain text  / Fasta format
• Retrieve the sequence logo from the alignment
• Taxonomic tree view of all Swiss-Prot/TrEMBL entries matching PS01254
• Retrieve a list of all Swiss-Prot/TrEMBL entries matching PS01254
• Scan Swiss-Prot/TrEMBL entries against PS01254
• view ligand binding statistics
FETUIN_2, PS01255; Fetuin family signature 2  (PATTERN)
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.
• Retrieve an alignment of Swiss-Prot true positive hits:
  Clustal format, color, condensed view  / Clustal format, color  / Clustal format, plain text  / Fasta format
• Retrieve the sequence logo from the alignment
• Taxonomic tree view of all Swiss-Prot/TrEMBL entries matching PS01255
• Retrieve a list of all Swiss-Prot/TrEMBL entries matching PS01255
• Scan Swiss-Prot/TrEMBL entries against PS01255
• view ligand binding statistics

References

1 Authors Kordis D., Turk V.
Title Phylogenomic analysis of the cystatin superfamily in eukaryotes and prokaryotes.
Source BMC Evol. Biol. 9:266-266(2009).
PubMed ID 19919722
DOI 10.1186/1471-2148-9-266
2 Authors Brown W.M., Dziegielewska K.M., Saunders N.R., Christie D.L., Nawratil P., Mueller-Esterl W.
Title The nucleotide and deduced amino acid structures of sheep and pig fetuin. Common structural features of the mammalian fetuin family.
Source Eur. J. Biochem. 205:321-331(1992).
PubMed ID 1372866
3 Authors Yang F., Chen Z.-L., Bergeron J.M., Cupples R.L., Friedrichs W.E.
Title Human alpha 2-HS-glycoprotein/bovine fetuin homologue in mice: identification and developmental regulation of the gene.
Source Biochim. Biophys. Acta 1130:149-156(1992).
PubMed ID 1373325
4 Authors Haasemann M., Nawratil P., Mueller-Esterl W.
Title Rat tyrosine kinase inhibitor shows sequence similarity to human alpha 2-HS glycoprotein and bovine fetuin.
Source Biochem. J. 274:899-902(1991).
PubMed ID 1707273
5 Authors Goto K., Yoshida K., Suzuki Y., Yamamoto K., Sinohara H.
Title Molecular cloning and sequencing of cDNA encoding plasma countertrypin, a member of mammalian fetuin family, from the Mongolian gerbil, Meriones unguiculatus.
Source J. Biochem. 121:619-625(1997).
PubMed ID 9133634
6 Authors Heiss A., DuChesne A., Denecke B., Groetzinger J., Yamamoto K., Renne T., Jahnen-Dechent W.
Title Structural basis of calcification inhibition by alpha 2-HS glycoprotein/fetuin-A. Formation of colloidal calciprotein particles.
Source J. Biol. Chem. 278:13333-13341(2003).
PubMed ID 12556469
DOI 10.1074/jbc.M210868200
7 Authors Aoki N., Deshimaru M., Kihara K., Terada S.
Title Snake fetuin: isolation and structural analysis of new fetuin family proteins from the sera of venomous snakes.
Source Toxicon 54:481-490(2009).
PubMed ID 19481564
DOI 10.1016/j.toxicon.2009.05.018
8 Authors Olivier E., Soury E., Ruminy P., Husson A., Parmentier F., Daveau M., Salier J.-P.
Title Fetuin-B, a second member of the fetuin family in mammals.
Source Biochem. J. 350:589-597(2000).
PubMed ID 10947975
9 Authors Liu J.-X., Zhai Y.-H., Geng F.-S., Xia J.-H., Gui J.-F.
Title Molecular characterization and expression pattern of fetuin-B in gibel carp (Carassius auratus gibelio).
Source Biochem. Genet. 46:620-633(2008).
PubMed ID 18751887
DOI 10.1007/s10528-008-9176-4

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