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.
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