Inter-α-inhibitor heavy chain-1 has an integrin-like 3D structure mediating immune regulatory activities and matrix stabilization during ovulation.

The Journal of Biological Chemistry
David C BriggsAnthony J Day

Abstract

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-contai...Continue Reading

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Citations

Jul 9, 2020·The Journal of Histochemistry and Cytochemistry : Official Journal of the Histochemistry Society·Megan S LordJohn M Whitelock

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Methods Mentioned

BETA
X-ray
size-exclusion chromatography
surface plasmon resonance
NMR
chip

Software Mentioned

AllosMod
PHENIX AutoSol
SEDFIT
Web GAG Builder
DIALS
BIAeval T200
PDBeFold
SEDPHAT
DATGNOM
AIMLESS

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