Combinatorial Control of Prion Protein Biogenesis by the Signal Sequence and Transmembrane Domain

Soo Jung Kim, Reza Rahbar, Ramanujan S. Hegde

Research output: Contribution to journalArticlepeer-review

86 Scopus citations

Abstract

The prion protein (PrP) is synthesized in three topologic forms at the endoplasmic reticulum. secPrP is fully translocated into the endoplasmic reticulum lumen, whereas NtmPrP and CtmPrP are single-spanning membrane proteins of opposite orientation. Increased generation of CtmPrP in either transgenic mice or humans is associated with the development of neurodegenerative disease. To study the mechanisms by which PrP can achieve three topologic outcomes, we analyzed the translocation of proteins containing mutations introduced into either the N-terminal signal sequence or potential transmembrane domain (TMD) of PrP. Although mutations in either domain were found to affect PrP topogenesis, they did so in qualitatively different ways. In addition to its traditional role in mediating protein targeting, the signal was found to play a surprising role in determining orientation of the PrP N terminus. By contrast, the TMD was found to influence membrane integration. Analysis of various signal and TMD double mutants demonstrated that the topologic consequence of TMD action was directly dependent on the previous, signal-mediated step. Together, these results reveal that PrP topogenesis is controlled at two discrete steps during its translocation and provide a framework for understanding how these steps act coordinately to determine the final topology achieved by PrP.

Original languageEnglish (US)
Pages (from-to)26132-26140
Number of pages9
JournalJournal of Biological Chemistry
Volume276
Issue number28
DOIs
StatePublished - Jul 13 2001
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint

Dive into the research topics of 'Combinatorial Control of Prion Protein Biogenesis by the Signal Sequence and Transmembrane Domain'. Together they form a unique fingerprint.

Cite this