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PDBsum entry 6fpy
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Structural protein
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PDB id
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6fpy
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References listed in PDB file
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Key reference
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Title
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Inter-α-Inhibitor heavy chain-1 has an integrin-Like 3d structure mediating immune regulatory activities and matrix stabilization during ovulation.
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Authors
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D.C.Briggs,
A.W.W.Langford-Smith,
H.L.Birchenough,
T.A.Jowitt,
C.M.Kielty,
J.J.Enghild,
C.Baldock,
C.M.Milner,
A.J.Day.
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Ref.
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J Biol Chem, 2020,
295,
5278-5291.
[DOI no: ]
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PubMed id
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Note: In the PDB file this reference is
annotated as "TO BE PUBLISHED". The citation details given above have
been manually determined.
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Abstract
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Inter-α-inhibitor is a proteoglycan essential for mammalian reproduction and
also plays a less well-characterized role in inflammation. It comprises two
homologous "heavy chains" (HC1 and HC2) covalently attached to
chondroitin sulfate on the bikunin core protein. Before ovulation, HCs are
transferred onto the polysaccharide hyaluronan (HA) to form covalent HC·HA
complexes, thereby stabilizing an extracellular matrix around the oocyte
required for fertilization. Additionally, such complexes form during
inflammatory processes and mediate leukocyte adhesion in the synovial fluids of
arthritis patients and protect against sepsis. Here using X-ray crystallography,
we show that human HC1 has a structure similar to integrin β-chains, with a von
Willebrand factor A domain containing a functional metal ion-dependent adhesion
site (MIDAS) and an associated hybrid domain. A comparison of the WT protein and
a variant with an impaired MIDAS (but otherwise structurally identical) by
small-angle X-ray scattering and analytical ultracentrifugation revealed that
HC1 self-associates in a cation-dependent manner, providing a mechanism for
HC·HA cross-linking and matrix stabilization. Surprisingly, unlike integrins,
HC1 interacted with RGD-containing ligands, such as fibronectin, vitronectin,
and the latency-associated peptides of transforming growth factor β, in a
MIDAS/cation-independent manner. However, HC1 utilizes its MIDAS motif to bind
to and inhibit the cleavage of complement C3, and small-angle X-ray
scattering-based modeling indicates that this occurs through the inhibition of
the alternative pathway C3 convertase. These findings provide detailed
structural and functional insights into HC1 as a regulator of innate immunity
and further elucidate the role of HC·HA complexes in inflammation and ovulation.
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