Coupled translocation events generate topological heterogeneity at the endoplasmic reticulum membrane

Kenneth Moss, Andrew Helm, Yun Lu, Alvina Bragin, William R. Skach

Research output: Contribution to journalArticlepeer-review

32 Scopus citations


Topogenic determinants that direct protein topology at the endoplasmic reticulum membrane usually function with high fidelity to establish a uniform topological orientation for any given polypeptide, Here we show, however, that through the coupling of sequential translocation events, native topogenic determinants are capable of generating two alternate transmembrane structures at the endoplasmic reticulum membrane. Using defined chimeric and epitope-tagged full-length proteins, we found that topogenic activities of two C-trans (type II) signal anchor sequences, encoded within the seventh and eighth transmembrane (TM) segments of human P-glycoprotein were directly coupled by an inefficient stop transfer (ST) sequence (TM7b) contained within the C-terminus half of TM7. Remarkably, these activities enabled TM7 to achieve both a single- and a double-spanning TM topology with nearly equal efficiency. In addition, ST and C-trans signal anchor activities encoded by TM8 were tightly linked to the weak ST activity, and hence topological fate, of TM7b. This interaction enabled TM8 to span the membrane in either a type I or a type II orientation. Pleiotropic structural features contributing tO this unusual topogenic behavior included 1) a short, flexible peptide loop connecting TM7a and TM7b, 2) hydrophobic residues within TM7b, and 3) hydrophilic residues between TM7b and TM8.

Original languageEnglish (US)
Pages (from-to)2681-2697
Number of pages17
JournalMolecular biology of the cell
Issue number9
StatePublished - Sep 1998
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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