Please use this identifier to cite or link to this item: http://hdl.handle.net/2381/36780
Title: The solution structures of native and patient monomeric human IgA1 reveal asymmetric extended structures: implications for function and IgAN disease.
Authors: Hui, G. K.
Wright, D. W.
Vennard, Owen L.
Rayner, L. E.
Pang, M.
Yeo, See Cheng
Gor, J.
Molyneux, Karen
Barratt, Jonathan
Perkins, S. J.
First Published: 2-Oct-2015
Publisher: Portland Press for Biochemical Society
Citation: Biochem J, 2015, 471 (2), pp. 167-185
Abstract: Native IgA1, for which no crystal structure is known, contains an O-galactosylated 23-residue hinge region that joins its Fab and Fc regions. IgA nephropathy (IgAN) is a leading cause of chronic kidney disease in developed countries. Because IgA1 in IgAN often has a poorly O-galactosylated hinge region, the solution structures of monomeric IgA1 from a healthy subject and three IgAN patients with four different O-galactosylation levels were studied. Analytical ultracentrifugation showed that all four IgA1 samples were monomeric with similar sedimentation coefficients, s(0)20,w. X-ray scattering showed that the radius of gyration (Rg) slightly increased with IgA1 concentration, indicating self-association, although their distance distribution curves, P(r), were unchanged with concentration. Neutron scattering indicated similar Rg values and P(r) curves, although IgA1 showed a propensity to aggregate in heavy water buffer. A new atomistic modelling procedure based on comparisons with 177000 conformationally-randomized IgA1 structures with the individual experimental scattering curves revealed similar extended Y-shaped solution structures for all four differentially-glycosylated IgA1 molecules. The final models indicated that the N-glycans at Asn(263) were folded back against the Fc surface, the C-terminal tailpiece conformations were undefined and hinge O-galactosylation had little effect on the solution structure. The solution structures for full-length IgA1 showed extended hinges and the Fab and Fc regions were positioned asymmetrically to provide ample space for the functionally-important binding of two FcαR receptors to its Fc region. Whereas no link between O-galactosylation and the IgA1 solution structure was detected, an increase in IgA1 aggregation with reduced O-galactosylation may relate to IgAN.
DOI Link: 10.1042/BJ20150612
ISSN: 0264-6021
eISSN: 1470-8728
Links: http://www.biochemj.org/content/471/2/167
http://hdl.handle.net/2381/36780
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © 2015 Authors This is an open access article published by Portland Press Limited and distributed under the Creative Commons Attribution License 3.0 ( http://creativecommons.org/licenses/by/3.0/ ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Appears in Collections:Published Articles, Dept. of Infection, Immunity and Inflammation



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