Kinetics of peptide binding to the class II MHC protein I-E(k)

Peter M. Kasson, Joshua D. Rabinowitz, Lutz Schmitt, Mark M. Davis, Harden M. McConnell

Research output: Contribution to journalArticle

48 Scopus citations

Abstract

Class II MHC glycoproteins bind short (7-25 amino acid) peptides in an extended type II polyproline-like conformation and present them for immune recognition. Because empty MHC is unstable, measurement of the rate of the second-order reaction between peptide and MHC is challenging. In this report, we use dissociation of a pre-bound peptide to generate the active, peptide- receptive form of the empty class II MHC molecule I-E(k). This allows us to measure directly the rate of reaction between active, empty I-E(k) and a set of peptides that vary in structure. We find that all peptides studied, despite having highly variable dissociation rates, bind with similar association rate constants. Thus, the rate-limiting step in peptide binding is minimally sensitive to peptide side-chain structure. An interesting complication to this simple model is that a single peptide can sometimes bind to I-E(k) in two kinetically distinguishable conformations, with the stable peptide-MHC complex isomer forming much more slowly than the less-stable one. This demonstrates that an additional free-energy barrier limits the formation of certain specific MHC-peptide complex conformations.

Original languageEnglish (US)
Pages (from-to)1048-1058
Number of pages11
JournalBiochemistry
Volume39
Issue number5
DOIs
StatePublished - Feb 8 2000

All Science Journal Classification (ASJC) codes

  • Biochemistry

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    Kasson, P. M., Rabinowitz, J. D., Schmitt, L., Davis, M. M., & McConnell, H. M. (2000). Kinetics of peptide binding to the class II MHC protein I-E(k). Biochemistry, 39(5), 1048-1058. https://doi.org/10.1021/bi9921337