The DeltaF508 cystic fibrosis mutation impairs domain-domain interactions and arrests post-translational folding of CFTR. Academic Article uri icon

Overview

abstract

  • Misfolding accounts for the endoplasmic reticulum-associated degradation of mutant cystic fibrosis transmembrane conductance regulators (CFTRs), including deletion of Phe508 (DeltaF508) in the nucleotide-binding domain 1 (NBD1). To study the role of Phe508, the de novo folding and stability of NBD1, NBD2 and CFTR were compared in conjunction with mutagenesis of Phe508. DeltaF508 and amino acid replacements that prevented CFTR folding disrupted the NBD2 fold and its native interaction with NBD1. DeltaF508 caused limited alteration in NBD1 conformation. Whereas nonpolar and some aliphatic residues were permissive, charged residues and glycine compromised the post-translational folding and stability of NBD2 and CFTR. The results suggest that hydrophobic side chain interactions of Phe508 are required for vectorial folding of NBD2 and the domain-domain assembly of CFTR, representing a combined co- and post-translational folding mechanism that may be used by other multidomain membrane proteins.

publication date

  • December 26, 2004

Research

keywords

  • Cystic Fibrosis
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Phenylalanine
  • Protein Folding
  • Sequence Deletion

Identity

Scopus Document Identifier

  • 11444266284

Digital Object Identifier (DOI)

  • 10.1038/nsmb882

PubMed ID

  • 15619635

Additional Document Info

volume

  • 12

issue

  • 1