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Authors
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K.Karmilin,
C.Schmitz,
M.Kuske,
H.Körschgen,
M.Olf,
K.Meyer,
A.Hildebrand,
M.Felten,
S.Fridrich,
I.Yiallouros,
C.Becker-Pauly,
R.Weiskirchen,
W.Jahnen-Dechent,
J.Floehr,
W.Stöcker.
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Vertebrate fetuins are multi-domain plasma-proteins of the cystatin-superfamily.
Human fetuin-A is also known as AHSG,
α2-Heremans-Schmid-glycoprotein. Gene-knockout in mice identified
fetuin-A as essential for calcified-matrix-metabolism and bone-mineralization.
Fetuin-B deficient mice, on the other hand, are female infertile due to zona
pellucida 'hardening' caused by the metalloproteinase ovastacin in unfertilized
oocytes. In wildtype mice fetuin-B inhibits the activity of ovastacin thus
maintaining oocytes fertilizable. Here we asked, if fetuins affect further
proteases as might be expected from their evolutionary relation to
single-domain-cystatins, known as proteinase-inhibitors. We show that fetuin-A
is not an inhibitor of any tested protease. In stark contrast, the closely
related fetuin-B selectively inhibits astacin-metalloproteinases such as meprins
and ovastacin, but not astacins of the tolloid-subfamily, nor any other
proteinase. The analysis of fetuin-B expressed in various mammalian cell types,
insect cells, and truncated fish-fetuin expressed in bacteria, showed that the
cystatin-like domains alone are necessary and sufficient for inhibition. This
report highlights fetuin-B as a specific antagonist of ovastacin and
meprin-metalloproteinases. Control of ovastacin was shown to be indispensable
for female fertility. Meprin inhibition, on the other hand, renders fetuin-B a
potential key-player in proteolytic networks controlling angiogenesis,
immune-defense, extracellular-matrix-assembly and general cell-signaling, with
implications for inflammation, fibrosis, neurodegenerative disorders and cancer.
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