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Crystal structures of T cell receptor chains related to rheumatoid arthritis

¹ Wadsworth Center, New York State Department of Health, and ² Department of Biomedical Sciences, School of Public Health, University at Albany, State University of New York, Empire State Plaza, Albany, New York 12201-0509, USA
³ Stroke Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA

(RECEIVED August 1, 2005; FINAL REVISION September 5, 2005; ACCEPTED September 6, 2005)

The crystal structures of the V17⁺ chains of two human T cell receptors (TCRs), originally derived from the synovial fluid (SF4) and tissue (C5–1) of a patient with rheumatoid arthritis (RA), have been determined in native (SF4) and mutant (C5–1_F104Y/C187S) forms, respectively. These TCR chains form homo-dimers in solution and in crystals. Structural comparison reveals that the main-chain conformations in the CDR regions of the C5–1 and SF4 V17 closely resemble those of a V17 JM22 in a bound form; however, the CDR3 region shows different conformations among these three V17 structures. At the side-chain level, conformational differences were observed at the CDR2 regions between our two ligand-free forms and the bound JM22 form. Other significant differences were observed at the V regions 8–12, 40–44, and 82–88 between C5–1/SF4 and JM22 V17, implying that there is considerable variability in the structures of very similar chains. Structural alignments also reveal a considerable variation in the V–C associations, and this may affect ligand recognition. The crystal structures also provide insights into the structure basis of T cell recognition of Mycoplasma arthritidis mitogen (MAM), a superantigen that may be implicated in the development of human RA. Structural comparisons of the V domains of known TCR structures indicate that there are significant similarities among V regions that are MAM-reactive, whereas there appear to be significant structural differences among those V regions that lack MAM-reactivity. It further reveals that CDR2 and framework region (FR) 3 are likely to account for the binding of TCR to MAM.

Keywords: TCR; crystal structure; superantigen; rheumatoid arthritis; Mycoplasma arthritidis mitogen; structure/function studies; proteins of the immune system; crystallography; protein crystallization; mutagenesis (site-directed and general); protein structures—new; sedimentation

Article published online ahead of print. Article and publication date are at http://www.proteinscience.org/cgi/doi/10.1110/ps.051748305.

Reprint requests to: Hongmin Li, Wadsworth Center, 150 New Scotland Avenue, CMS-1155, Albany, NY 12208, USA; e-mail: lih{at}wadsworth.org; fax: (518) 408-2190.

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