Biogenesis of CFTR and other polytopic membrane proteins: New roles for the ribosome-translocon complex

H. Sadlish, William Skach

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Polytopic protein biogenesis represents a critical, yet poorly understood area of modern biology with important implications for human disease. Inherited mutations in a growing array of membrane proteins frequently lead to improper folding and/or trafficking. The cystic fibrosis transmembrane conductance regulator (CFTR) is a primary example in which point mutations disrupt CFTR folding and lead to rapid degradation in the endoplasmic reticulum (ER). It has been difficult, however, to discern the mechanistic principles of such disorders, in part, because membrane protein folding takes place coincident with translation and within a highly specialized environment formed by the ribosome, Sec61 translocon, and the ER membrane. This ribosome-translocon complex (RTC) coordinates the synthesis, folding, orientation and integration of transmembrane segments across and into the ER membrane. At the same time, RTC function is controlled by specific sequence determinants within the nascent polypeptide. Recent studies of CFTR and other native membrane proteins have begun to define novel variations in translocation pathways and to elucidate the specific steps that establish complex topology. This article will attempt to reconcile advances in our understanding of protein biogenesis with emerging models of RTC function. In particular, it will emphasize how information within the nascent polypeptide is interpreted by and in turn controls RTC dynamics to generate the broad structural and functional diversity observed for naturally occurring membrane proteins.

Original languageEnglish (US)
Pages (from-to)115-126
Number of pages12
JournalJournal of Membrane Biology
Volume202
Issue number3
DOIs
StatePublished - Dec 2004

Fingerprint

Cystic Fibrosis Transmembrane Conductance Regulator
Ribosomes
Membrane Proteins
Endoplasmic Reticulum
Peptides
Membranes
Protein Folding
Point Mutation
Proteins
Mutation

Keywords

  • Biogenesis
  • CFTR
  • Cystic fibrosis
  • Membrane protein
  • Polytopic protein
  • Topogenesis
  • Translocon

ASJC Scopus subject areas

  • Biophysics
  • Physiology
  • Cell Biology

Cite this

Biogenesis of CFTR and other polytopic membrane proteins : New roles for the ribosome-translocon complex. / Sadlish, H.; Skach, William.

In: Journal of Membrane Biology, Vol. 202, No. 3, 12.2004, p. 115-126.

Research output: Contribution to journalArticle

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