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Crystallographic Structure of a Rheumatoid Arthritis MHC Susceptibility Allele, HLA-DR1 (DRB1*0101), Complexed with the Immunodominant Determinant of Human Type II Collagen¹

Edward F. Rosloniec^2,*,,, Robert A. Ivey, III^2,3,, Karen B. Whittington^*, Andrew H. Kang^*, and Hee-Won Park^4,

^* Veterans Affairs Medical Center, Memphis, TN 38104; Department of Medicine and Department of Pathology, University of Tennessee Health Science Center, Memphis, TN 38163; and Department of Structural Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105

The expression of HLA-DR1 (DRB1*0101) is associated with an enhanced risk for developing rheumatoid arthritis (RA). To study its function, we have solved the three-dimensional structure of HLA-DR1 complexed with a candidate RA autoantigen, the human type II collagen peptide CII (259–273). Based on these structural data, the CII peptide is anchored by Phe²⁶³ at the P1 position and Glu²⁶⁶ at P4. Surprisingly, the Lys at the P2 position appears to play a dual role by participating in peptide binding via interactions with DRB1-His⁸¹ and Asn⁸², and TCR interaction, based on functional assays. The CII peptide is also anchored by the P4 Glu²⁶⁶ residue through an ionic interaction with DRB1-Arg⁷¹ and Glu²⁸. Participation of DRB1-Arg⁷¹ is significant because it is part of the shared epitope expressed by DR alleles associated with RA susceptibility. Potential anchor residues at P6 and P9 of the CII peptide are both Gly, and the lack of side chains at these positions appears to result in both a narrower binding groove with the peptide protruding out of the groove at this end of the DR1 molecule. From the TCR perspective, the P2-Lys²⁶⁴, P5-Arg²⁶⁷, and P8-Lys²⁷⁰ residues are all oriented away from the binding groove and collectively represent a positive charged interface for CII-specific TCR binding. Comparison of the DR1-CII structure to a DR1-hemagglutinin peptide structure revealed that the binding of these two peptides generates significantly different interfaces for the interaction with their respective Ag-specific TCRs.

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 in part by grants from the Department of Veterans Affairs, Memphis, TN (to E.F.R. and A.H.K.), by U.S. Public Health Service Grants AR39166 and AR47379 (to E.F.R. and A.H.K.) from the National Institute for Arthritis and Musculoskeletal Diseases, and the American Lebanese Syrian Associated Charities.

² E.F.R. and R.A.I. contributed equally to this work.

³ Current address: Roskamp Institute, 2040 Whitfield Avenue, Sarasota, FL, 34243.

⁴ Address correspondence and reprint requests to Dr. Hee-Won Park at the current address: Structural Genomics Consortium, 5th Floor, Room 512, Banting Building, 100 College Street, Toronto, Ontario M5G 1L5, Canada. E-mail address: heewon.park{at}utoronto.ca

⁵ Abbreviations used in this paper: RA, rheumatoid arthritis; CII, type II collagen; CIA, collagen-induced arthritis; OcG, octyl glucoside; PB, phosphate buffer; HA, hemagglutinin.