Hui, GK;
Wright, DW;
Vennard, OL;
Rayner, LE;
Pang, M;
Yeo, SC;
Gor, J;
... Perkins, SJ; + view all
(2015)
The solution structures of native and patient monomeric human IgA1 reveal asymmetric extended structures: implications for function and IgAN disease.
Biochemical Journal
, 471
(2)
pp. 167-185.
10.1042/BJ20150612.
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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.
| Type: | Article |
|---|---|
| Title: | The solution structures of native and patient monomeric human IgA1 reveal asymmetric extended structures: implications for function and IgAN disease |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1042/BJ20150612 |
| Publisher version: | http://dx.doi.org/10.1042/BJ20150612 |
| Additional information: | © 2015 Authors. This is an open access article published by Portland Press Limited and distributed under the Creative Commons Attribution License 3.0. |
| Keywords: | X-ray scattering, analytical ultracentrifugation, antibody, constrained modelling, human immunoglobulin A1 (IgA1), immunoglobulin A (IgA) nephropathy, neutron scattering |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology UCL > Provost and Vice Provost Offices > UCL BEAMS UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1473271 |
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