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Large Scale Mass Spectrometric Profiling of Peptides Eluted from HLA Molecules Reveals N-Terminal-Extended Peptide Motifs¹

Hernando Escobar^2,*, David K. Crockett^2,, Eduardo Reyes-Vargas^*, Andres Baena, Alan L. Rockwood^*,, Peter E. Jensen^*, and Julio C. Delgado^3,*,

^* Department of Pathology, University of Utah, Salt Lake City, UT 84112; Associated Regional and University Pathologists (ARUP) Institute for Clinical and Experimental Pathology, Salt Lake City, UT 84108; and Department of Microbiology and Immunology, Albert Einstein College of Medicine, New York, NY 10461

The majority of >2000 HLA class I molecules can be clustered according to overlapping peptide binding specificities or motifs recognized by CD8⁺ T cells. HLA class I motifs are classified based on the specificity of residues located in the P2 and the C-terminal positions of the peptide. However, it has been suggested that other positions might be relevant for peptide binding to HLA class I molecules and therefore be used for further characterization of HLA class I motifs. In this study we performed large-scale sequencing of endogenous peptides eluted from K562 cells (HLA class I null) made to express a single HLA molecule from HLA-B*3501, -B*3502, -B*3503, -B*3504, -B*3506, or -B*3508. Using sequence data from >1,000 peptides, we characterized novel peptide motifs that include dominant anchor residues extending to all positions in the peptide. The length distribution of HLA-B35-bound peptides included peptides of up to 15 residues. Remarkably, we determined that some peptides longer than 11 residues represented N-terminal-extended peptides containing an appropriate HLA-B35 peptide motif. These results provide evidence for the occurrence of endogenous N-terminal-extended peptide-HLA class I configurations. In addition, these results expand the knowledge about the identity of anchor positions in HLA class I-associated peptides that can be used for characterization of HLA class I motifs.

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 Grants AI33614 and AI20554 (to P.E.J.) and funds from the Associated Regional and University Pathologists (ARUP) Institute for Clinical and Experimental Pathology (to D.K.C., A.L.R., P.E.J., and J.C.D.).

² H.E. and D.K.C. contributed equally to the study.

³ Address correspondence and reprint requests to Dr. Julio C. Delgado, University of Utah, Department of Pathology, 15 North Medical Drive East, Suite 2100, Salt Lake City, UT 84112. E-mail address: julio.delgado{at}path.utah.edu

⁴ Abbreviations used in this paper: ER, endoplasmic reticulum; ERAAP, ER aminopeptidase associated with Ag processing; ERAP1, ERAAP human otholog; Q-TOF, quadrupole time-of-flight.

⁵ The online version of this article contains supplemental material.