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Twelve Chloride Ions Drive Assembly of Human alpha345 Collagen IV NC1 domain
Structural highlights
Publication Abstract from PubMedOur recent work identified a genetic variant of the alpha345 hexamer of the collagen IV scaffold that is present in patients with glomerular basement membrane diseases, Goodpasture's disease (GP) and Alport syndrome (AS), and phenocopies AS in knock-in mice (see Companion Paper I). To understand the context of this "Zurich" variant, an 8-amino acid appendage, we developed a construct of the wild-type alpha345 hexamer using single-chain NC1 trimer technology, which allowed us to solve a crystal structure of this key connection module. The alpha345 hexamer structure revealed a ring of twelve chloride ions at the trimer-trimer interface, analogous to the collagen alpha121 hexamer, and the location of the 170 AS variants. The hexamer surface is marked by multiple pores and crevices that are potentially accessible to small molecules. Loop-crevice-loop (LCL) features constitute bioactive sites, where pathogenic pathways converge that are linked to Alport and GP diseases, and, potentially, diabetic nephropathy. In Companion Paper III, we demonstrate that these sites exhibit conformational plasticity, a dynamic property underlying assembly of bioactive sites and hexamer dysfunction. The alpha345 hexamer structure is a platform to decipher how variants cause AS, and how hypoepitopes can be triggered causing GP. Furthermore, the bioactive sites, along with the pores and crevices on the hexamer surface, are prospective targets for therapeutic interventions. Collagen IV(alpha345) dysfunction in glomerular basement membrane diseases. II. Crystal structure of the alpha345 hexamer.,Boudko SP, Bauer R, Chetyrkin SV, Ivanov S, Smith J, Voziyan PA, Hudson BG J Biol Chem. 2021 Mar 25:100591. doi: 10.1016/j.jbc.2021.100591. PMID:33775698[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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