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Reconstitution by MHC-restricted peptides of HLA-A2 heavy chain with β2-microglobulin, in vitro

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Abstract

CYTOTOXIC T lymphocytes kill virally infected cells when they detect antigenic fragments presented by class I major histocompatibility complex (MHC) antigens (HLA in humans). The crystal structures of HLA-A2 and HLA-Aw68 reveal that peptide-antigen forms an integral part of the HLA structure, being retained in a prominent groove even after purification and crystallization1–3. Here we report that the heavy chain and β2-microglobulin of HLA-A2, after separation and fractionation in denaturants, reassemble efficiently under renaturing conditions only in the presence of MHC-restricted4 peptides. A complex of heavy chain, β2-microgIobulin, and viral peptide in the ratio 1:1:1 is formed in up to 46% yield. Reconstitution is not stimulated by either of two peptides not restricted to HLA-A2. The reconstituted complex of HLA-A2 and the influenza virus (B/Lee/40) nucleoprotein peptide, Np (85–94), crystallizes under conditions previously used to crystallize HLA-A2 (ref. 5). Peptide-linked folding and assembly suggests mechanisms for the unusual capacity of HLA to bind many peptides of diverse sequence.

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Author notes

  1. Kenneth C. Parker

    Present address: Biological Resources Branch, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, 20892, USA

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Harvard University, 7 Divinity Avenue, Cambridge, Massachusetts, 02138, USA

    Michael L. Silver, Kenneth C. Parker & Don C. Wiley

  2. Howard Hughes Medical Institute, Harvard University, 7 Divinity Avenue, Cambridge, Massachusetts, 02138, USA

    Don C. Wiley

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  1. Michael L. Silver
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  2. Kenneth C. Parker
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  3. Don C. Wiley
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Silver, M., Parker, K. & Wiley, D. Reconstitution by MHC-restricted peptides of HLA-A2 heavy chain with β2-microglobulin, in vitro. Nature 350, 619–622 (1991). https://doi.org/10.1038/350619a0

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  • DOI: https://doi.org/10.1038/350619a0

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