Efficient folding of the FcεRI α-chain membrane-proximal domain D2 depends on the presence of the N-terminal domain D1

Luca Vangelista, Michela Cesco-Gaspere, Doriano Lamba, Oscar Burrone

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Human high affinity receptor for IgE is a membrane glycoprotein multi-chain complex presenting two extracellular Ig modules in its α-chain (D1D2). The receptor IgE binding region is located within the membrane-proximal module D2, while the N-terminal module D1 appears to promote an optimal receptor conformation for IgE binding. To understand the structural relationship between the two modules, we dissected FcεRI α-chain into its discrete Ig units and expressed them in mammalian cells. Unexpectedly, D2 was secreted as a disulphide-linked dimer, while D1 was monomeric. Active secretion and full glycosylation of dimeric D2 suggest a native-like conformation of the protein, justifying the escape from the endoplasmic reticulum/Golgi quality control systems. We then propose a domain-swapping model for D2, in which two interdigitated polypeptide chains assume the overall conformation of two Ig modules, as observed for rat CD2 N-terminal domain. Fusion of an unrelated Ig fold moiety at the N terminus of D2 did not interfere with its dimerisation. While D1D2 assumes a correct fold, co-expression of both isolated domains in the same cell did not restore monomeric folding of D2. Thus, D1 appears to assist the appropriate folding of FcεRI α-chain, acting as an uncleavable intramolecular chaperone-like block towards D2.

Original languageEnglish
Pages (from-to)815-825
Number of pages11
JournalJournal of Molecular Biology
Volume322
Issue number4
DOIs
Publication statusPublished - Jan 1 2002

Keywords

  • Domain swapping
  • FcεRI
  • Folding in vivo
  • Intramolecular chaperone
  • Molecular modelling

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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