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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

DOI: 10.1074/jbc.RA119.011916 DOI Help

Authors: Jan J. Enghild (University of Manchester) , Clair Baldock (University of Manchester) , Caroline M. Milner (University of Manchester) , Anthony J. Day (University of Manchester) , David C. Briggs (University of Manchester) , Alexander W. W. Langford-Smith (University of Manchester) , Holly L. Birchenough (University of Manchester) , Thomas A. Jowitt (University of Manchester) , Cay M. Kielty (University of Manchester)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Biological Chemistry

State: Published (Approved)
Published: April 2020

Open Access Open Access

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-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.

Journal Keywords: extracellular matrix; hyaluronan; inflammation; innate immunity; protein stability; proteoglycan; reproduction; X-ray crystallography; small-angle X-ray scattering (SAXS); Inter-α-inhibitor Heavy Chain

Subject Areas: Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography , I22-Small angle scattering & Diffraction

Other Facilities: DESY PETRA III

Added On: 27/04/2020 14:30

Documents:
J. Biol. Chem.-2020-Briggs-5278-91.pdf

Discipline Tags:

Life Sciences & Biotech Structural biology

Technical Tags:

Diffraction Scattering Macromolecular Crystallography (MX) Small Angle X-ray Scattering (SAXS)