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Implications of the Near-Planar Solution Structure of Human Myeloma Dimeric IgA1 for Mucosal Immunity and IgA Nephropathy¹

Alexandra Bonner^*, Patricia B. Furtado^*, Adel Almogren, Michael A. Kerr and Stephen J. Perkins^2,*

^* Department of Biochemistry and Molecular Biology, University College London, London, United Kingdom; Department of Pathology, College of Medicine and King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia; and Department of Clinical Biochemistry and Immunology, General Infirmary, Leeds, United Kingdom

IgA is unique in being able to form a diverse range of polymeric structures. Increases in the levels of dimeric IgA1 (dIgA1) in serum have been implicated in diseases such as IgA nephropathy. We have determined the solution structure for dIgA1 by synchrotron x-ray and neutron scattering and analytical ultracentrifugation. The Guinier radius of gyration (R_G) of 7.60–8.65 nm indicated that the two monomers within dIgA1 are arranged in an extended conformation. The distance distribution curve P(r) gave an overall length (L) of 22–26 nm. These results were confirmed by the sedimentation coefficient and frictional ratio of dIgA1. Constrained scattering modeling starting from the IgA1 monomer solution structure revealed a near-planar dimer structure for dIgA1. The two Fc regions form a slightly bent arrangement in which they form end-to-end contacts, and the J chain was located at this interface. This structure was refined by optimizing the position of the four Fab regions. From this, the best-fit solution structures show that the four Fab Ag-binding sites are independent of one another, and the two Fc regions are accessible to receptor binding. This arrangement allows dIgA1 to initiate specific immune responses by binding to FcRI receptors, while still retaining Ag-binding ability, and to be selectively transported to mucosal surfaces by binding to the polymeric Ig receptor to form secretory IgA. A mechanism for the involvement of dIgA1 oligomers in the pathology of IgA nephropathy is discussed in the light of this near-planar structure.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Biotechnology and Biological Sciences Research Council.

² Address correspondence and reprint requests to Dr. Stephen J. Perkins, Department of Biochemistry and Molecular Biology, Darwin Building, University College London, Gower Street, London WC1E 6BT, U.K. E-mail address: s.perkins{at}medsch.ucl.ac.uk

³ Abbreviations used in this paper: SC, secretory component; dIgA1, dimeric IgA1; SIgA, secretory IgA; pIgR, polymeric Ig receptor; IgAN, IgA nephropathy; HSA, human serum albumin.