Efficient folding of the FcepsilonRI alpha-chain membrane-proximal domain D2 depends on the presence of the N-terminal domain D1. (Articolo in rivista)

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  • Efficient folding of the FcepsilonRI alpha-chain membrane-proximal domain D2 depends on the presence of the N-terminal domain D1. (Articolo in rivista) (literal)
Anno
  • 2002-01-01T00:00:00+01:00 (literal)
Alternative label
  • Vangelista L. 1, Cesco-Gaspere M. 2, Lamba D. 3, Burrone O. 2 (2002)
    Efficient folding of the FcepsilonRI alpha-chain membrane-proximal domain D2 depends on the presence of the N-terminal domain D1.
    in Journal of Molecular Biology
    (literal)
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  • Vangelista L. 1, Cesco-Gaspere M. 2, Lamba D. 3, Burrone O. 2 (literal)
Pagina inizio
  • 815 (literal)
Pagina fine
  • 825 (literal)
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  • We found that D1 plays an important role for the achievement of proper FcepsilonRIalpha folding. Expression of D2 alone led to a dimeric protein stabilized by S-S bonds that was actively glycosylated and secreted. Our results indicate that the N-terminal Ig module act in cis as an intra-molecular chaperone-like block towards the membrane-proximal Ig module. Further studies are necessary to provide the experimental comprehensive picture required to carefully design efficient drugs acting at the IgE-FcepsilonRI interface. Impact Factor (2002): 5.359 Citations: 3 (literal)
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  • 322 (literal)
Rivista
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  • The last decade has seen a wealth of immunological and biochemical studies aimed at the characterization of the binding between IgE and its high-affinity receptor, FcepsilonRI. IgE-FcepsilonRI complex formation is a major molecular event in atopic allergy. IgE-FcepsilonRI binding connects allergen recognition to cellular triggering, ultimately leading to disease manifestations. Consequently, pharmacological intervention at this site is of universal relevance for atopic allergy. The complexity of IgE-FcepsilonRI binding, together with the difficulty in obtaining fully functional recombinant IgE and FcepsilonRI derivatives, often led to difficulty in data interpretation. Most of the current knowledge on the IgE-FcepsilonRI recognition mode derives from long-lasting efforts in the field of structural biology. The data accumulated to date predict that IgE and FcepsilonRI use their modular architecture to approach each other in an asymmetric stepwise manner determining a 1:1 stoichiometry. This recognition appears to be enhanced by conformational changes occurring upon binding, leading to the well-known high-affinity. In human FcepsilonRIalpha, D1, the N-terminal Ig module, has been reported to contribute to the appropriate orientation of D2, the membrane-proximal Ig module, indirectly promoting high IgE affinity. In an attempt to elucidate the relationship between D1 and D2, we dissected the receptor into two modular units and analysed them independently or in co-expression. (literal)
Note
  • ISI Web of Science (WOS) (literal)
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  • 1 DIBIT-HSR, 2 ICGEB, 3 IC-CNR (literal)
Titolo
  • Efficient folding of the FcepsilonRI alpha-chain membrane-proximal domain D2 depends on the presence of the N-terminal domain D1. (literal)
Abstract
  • Human high affinity receptor for IgE is a membrane glycoprotein multichain complex presenting two extracellular Ig modules in its alpha-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 FcepsilonRI alpha-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 FcepsilonRI alpha-chain, acting as an uncleavable intramolecular chaperone-like block towards D2. (literal)
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