ArticleThe Journal of biological chemistry2020
Inter-α-inhibitor heavy chain-1 has an integrin-like 3D structure mediating immune regulatory activities and matrix stabilization during ovulation.
Article in The Journal of biological chemistry, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 34 citations in OpenAlex.
- Migration of immune cells in tumors and inflammation: molecular mechanisms and therapeutic targets.Signal transduction and targeted therapy · 2026Review
- The hyaluronan receptor CD44 drives COVID-19 severity through its regulation of neutrophil migration.PLoS pathogens · 2026Article
- Longitudinal plasma proteome profiling after allogeneic hematopoietic stem cell transplantation: heterogeneous development and associations with acute GvHD.Frontiers in immunology · 2026Article
- The hyaluronan receptor CD44 drives COVID-19 severity through its regulation of neutrophil migration.bioRxiv : the preprint server for biology · 2025Article
- Infectious parvovirus B19 circulates in the blood coated with active host protease inhibitors.Nature communications · 2024Article
- Inter-alpha-trypsin inhibitor (IαI) and hyaluronan modifications enhance the innate immune response to influenza virus in the lung.Matrix biology : journal of the International Society for Matrix Biology · 2024Article
- The function of the inter-alpha-trypsin inhibitors in the development of disease.Frontiers in medicine · 2024Review
- Updated protein domain annotation of the PARP protein family sheds new light on biological function.Nucleic acids research · 2023Article
- Serum Proteomic Profiles Reflect the Stages of Myxomatous Mitral Valve Disease in Dogs.International journal of molecular sciences · 2023Article
- Article
- Synergy between a cytoplasmic vWFA/VIT protein and a WD40-repeat F-box protein controls development inFrontiers in cell and developmental biology · 2023Article
- Dysfunctional Extracellular Matrix Remodeling Supports Perianal Fistulizing Crohn's Disease by a Mechanoregulated Activation of the Epithelial-to-Mesenchymal Transition.Cellular and molecular gastroenterology and hepatology · 2023Article
- MS-proteomics provides insight into the host responses towards alginate microspheres.Materials today. Bio · 2022Article
- Quantifying In Situ Structural Stabilities of Human Blood Plasma Proteins Using a Novel Iodination Protein Stability Assay.Journal of proteome research · 2022Article
- Defining the versican interactome in lung health and disease.American journal of physiology. Cell physiology · 2022Review
- Human adaptation to high altitude: a review of convergence between genomic and proteomic signatures.Human genomics · 2022Review
- Review
- Evolutionary, proteomic, and experimental investigations suggest the extracellular matrix of cumulus cells mediates fertilization outcomes†.Biology of reproduction · 2021Article
- The Function of Cumulus Cells in Oocyte Growth and Maturation and in Subsequent Ovulation and Fertilization.Cells · 2021Review
- ITIH4 acts as a protease inhibitor by a novel inhibitory mechanism.Science advances · 2021Article
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Authors and funding
9 authors at 2 institutions in 2 countries.
Funding
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.
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