The solution structures of native and patient monomeric human IgA1 reveal asymmetric extended structures: implications for function and IgAN disease..pdf (2.39 MB)
The solution structures of native and patient monomeric human IgA1 reveal asymmetric extended structures: implications for function and IgAN disease.
journal contribution
posted on 2016-02-18, 11:13 authored 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. PerkinsNative 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.
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Citation
Biochem J, 2015, 471 (2), pp. 167-185Author affiliation
/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Infection, Immunity and InflammationVersion
- VoR (Version of Record)
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Biochem JPublisher
Portland Press for Biochemical Societyissn
0264-6021eissn
1470-8728Acceptance date
2015-08-12Copyright date
2015Available date
2016-02-18Publisher DOI
Publisher version
http://www.biochemj.org/content/471/2/167Language
enAdministrator link
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Keywords
X-ray scatteringanalytical ultracentrifugationantibodyconstrained modellinghuman immunoglobulin A1 (IgA1)immunoglobulin A (IgA) nephropathyneutron scatteringCrystallography, X-RayFemaleGlomerulonephritis, IGAHumansImmunoglobulin AImmunoglobulin Fab FragmentsImmunoglobulin Fc FragmentsMaleModels, MolecularProtein Aggregation, PathologicalProtein Structure, Quaternary
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