The solution structures of native and patient monomeric human IgA1 reveal asymmetric extended structures: implications for function and IgAN disease..pdf (2.39 MB)
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The solution structures of native and patient monomeric human IgA1 reveal asymmetric extended structures: implications for function and IgAN disease.

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journal contribution
posted on 18.02.2016, 11:13 by G. K. Hui, D. W. Wright, Owen L. Vennard, L. E. Rayner, M. Pang, See Cheng Yeo, J. Gor, Karen Molyneux, Jonathan Barratt, S. J. Perkins
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.

History

Citation

Biochem J, 2015, 471 (2), pp. 167-185

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Infection, Immunity and Inflammation

Version

VoR (Version of Record)

Published in

Biochem J

Publisher

Portland Press for Biochemical Society

issn

0264-6021

eissn

1470-8728

Acceptance date

12/08/2015

Copyright date

2015

Available date

18/02/2016

Publisher version

http://www.biochemj.org/content/471/2/167

Language

en