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Cutting Edge: HLA-DM Functions through a Mechanism That Does Not Require Specific Conserved Hydrogen Bonds in Class II MHC-Peptide Complexes¹

Zemin Zhou^2,*,, Kari A. Callaway^2,*, Dominique A. Weber and Peter E. Jensen^3,*,

^* Department of Pathology, University of Utah, Salt Lake City, UT 84112; Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322; ARUP Laboratories, University of Utah, Salt Lake City, UT 84108; and College of Life Science and Technology, Huazhong Agricultural University, Wuhan, China 430070

HLA-DM catalyzes peptide dissociation and exchange in class II MHC molecules through a mechanism that has been proposed to involve the disruption of specific components of the conserved hydrogen bond network in MHC-peptide complexes. HLA-DR1 molecules with alanine substitutions at each of the six conserved H- bonding positions were expressed in cells, and susceptibility to DM catalytic activity was evaluated by measuring the release of CLIP. The mutants N62A, N69A, R76A, and βH81A DR1 were fully susceptible to DM-mediated CLIP release, and βN82A resulted in spontaneous release of CLIP. Using recombinant soluble DR1 molecules, the amino acid βN82 was observed to contribute disproportionately in stabilizing peptide complexes. Remarkably, the catalytic potency of DM with each β-chain mutant was equal to or greater than that observed with wild-type DR1. Our results support the conclusion that no individual component of the conserved hydrogen bond network plays an essential role in the DM catalytic mechanism.

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 National Institutes of Health Research Grants AI30554 and AI33614.

² Z.Z. and K.A.C. contributed equally to this study.

³ Address correspondence and reprint requests to Dr. Peter E. Jensen, Department of Pathology, University of Utah, Emma Eccles Jones Medical Research Building, 15 North Medical Drive East, Suite 1100, Salt Lake City, UT 84112-5650. E-mail address: peter.jensen{at}path.utah.edu

⁴ Abbreviations used in this paper: Ii, invariant chain; s, soluble (prefix); WT, wild type.

⁵ The online version of this article contains supplemental material.