A three-step kinetic mechanism for peptide binding to MHC class II proteins

Ravi V. Joshi, Jennifer A. Zarutskie, Lawrence J. Stern

Research output: Contribution to journalArticlepeer-review

58 Scopus citations


Peptide binding reactions of class II MHC proteins exhibit unusual kinetics, with extremely slow apparent rate constants for the overall association (< 100 M-1 s-1) and dissociation (< 10-5 s-1) processes. Various linear and branched pathways have been proposed to account for these data. Using fluorescence resonance energy transfer between tryptophan residues in the MHC peptide binding site and aminocoumarin-labeled peptides, we measured real-time kinetics of peptide binding to empty class II MHC proteins. Our experiments identified an obligate intermediate in the binding reaction. The observed kinetics were consistent with a binding mechanism that involves an initial bimolecular binding step followed by a slow unimolecular conformational change. The same mechanism is observed for different peptide antigens. In addition, we noted a reversible inactivation of the empty MHC protein that competes with productive binding. The implications of this kinetic mechanism for intracellular antigen presentation pathways are discussed.

Original languageEnglish (US)
Pages (from-to)3751-3762
Number of pages12
Issue number13
StatePublished - Apr 4 2000

ASJC Scopus subject areas

  • Biochemistry


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