PDBsum entry 6fpy

Structural protein

PDB id: 6fpy

Contents

Protein chains

600 a.a.

Ligands

GOL ×6

Metals

_MG ×2

Waters ×345

PDB id:

6fpy

Name:

Structural protein

Title:

Inter-alpha-inhibitor heavy chain 1, wild type

Structure:

Inter-alpha-trypsin inhibitor heavy chain h1. Chain: a, b. Synonym: inter-alpha-inhibitor heavy chain 1,inter-alpha-trypsin inhibitor complex component iii,serum-derived hyaluronan-associated protein,shap. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: itih1, ighep1. Expressed in: escherichia coli k-12. Expression_system_taxid: 83333. Expression_system_variant: shuffle.

Resolution:

2.34Å R-factor: 0.233 R-free: 0.261

Authors:

D.C.Briggs,A.J.Day

Key ref:

D.C.Briggs et al. (2020). Inter-α-inhibitor heavy chain-1 has an integrin-like 3D structure mediating immune regulatory activities and matrix stabilization during ovulation. J Biol Chem, 295, 5278-5291. PubMed id: 32144206 DOI: 10.1074/jbc.RA119.011916

Date:

12-Feb-18 Release date: 27-Feb-19

Protein chains

P19827  (ITIH1_HUMAN) -  Inter-alpha-trypsin inhibitor heavy chain H1 from Homo sapiens

Seq: 911 a.a.

Struc: 600 a.a.

DOI no: 10.1074/jbc.RA119.011916

J Biol Chem 295:5278-5291 (2020)

PubMed id: 32144206

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

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.

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.