MHC class II function preserved by low-affinity peptide interactions preceding stable binding

Scheherazade Sadegh-Nasseri, Lawrence J. Stern, Don C. Wiley, Ronald N. Germain

Research output: Contribution to journalArticlepeer-review

Abstract

MAJOR histocompatibility complex class II molecules and their peptide ligands show unusual interaction kinetics, with slow association and dissociation rates that yield an apparent equilibrium constant of ∼10 -6-10-8 M (refs 1-5). However, there is evidence for a specific, rapidly formed, short-lived complex6. The altered migration on SDS-polyacrylamide gel electrophoresis of class II molecules upon stable peptide binding7-9 has led to the hypothesis that the two kinetically distinguishable types of class II-peptide complexes correspond to different structures. In accord with this model, we demonstrate here that insect cell-derived HLA-DR1 class II molecules show fast, almost stoichiometric occupancy with rapidly dissociating peptide while remaining sensitive to SDS-induced chain dissociation. The same DR1 molecules slowly and quantitatively form long-lived complexes resistant to SDS-induced denaturation. Surprisingly, low-affinity interaction with peptide protects class II from denaturation at physiological temperature, a finding that has implications for understanding the role of invariant chain in the intracellular behaviour of class II molecules.

Original languageEnglish (US)
Pages (from-to)647-650
Number of pages4
JournalNature
Volume370
Issue number6491
DOIs
StatePublished - Jan 1 1994
Externally publishedYes

ASJC Scopus subject areas

  • General

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