Static retention of the lumenal monotopic membrane protein torsinA in the endoplasmic reticulum

Abigail B. Vander Heyden, Teresa V. Naismith, Erik L. Snapp, Phyllis I. Hanson

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

TorsinA is a membrane-associated enzyme in the endoplasmic reticulum (ER) lumen that is mutated in DYT1 dystonia. How it remains in the ER has been unclear. We report that a hydrophobic N-terminal domain (NTD) directs static retention of torsinA within the ER by excluding it from ER exit sites, as has been previously reported for short transmembrane domains (TMDs). We show that despite the NTD's physicochemical similarity to TMDs, it does not traverse the membrane, defining torsinA as a lumenal monotopic membrane protein and requiring a new paradigm to explain retention. ER retention and membrane association are perturbed by a subset of nonconservative mutations to the NTD, suggesting that a helical structure with defined orientation in the membrane is required. TorsinA preferentially enriches in ER sheets, as might be expected for a lumenal monotopic membrane protein. We propose that the principle of membrane-based protein sorting extends to monotopic membrane proteins, and identify other proteins including the monotopic lumenal enzyme cyclooxygenase 1 (prostaglandin H synthase 1) that share this mechanism of retention with torsinA.

Original languageEnglish (US)
Pages (from-to)3217-3231
Number of pages15
JournalEMBO Journal
Volume30
Issue number16
DOIs
StatePublished - Aug 17 2011

Fingerprint

Endoplasmic Reticulum
Membrane Proteins
Membranes
Cyclooxygenase 1
Enzymes
Sorting
Dystonia
Protein Transport
Proteins
Mutation

Keywords

  • endoplasmic reticulum
  • membranes
  • protein sorting

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)
  • Medicine(all)

Cite this

Vander Heyden, A. B., Naismith, T. V., Snapp, E. L., & Hanson, P. I. (2011). Static retention of the lumenal monotopic membrane protein torsinA in the endoplasmic reticulum. EMBO Journal, 30(16), 3217-3231. https://doi.org/10.1038/emboj.2011.233

Static retention of the lumenal monotopic membrane protein torsinA in the endoplasmic reticulum. / Vander Heyden, Abigail B.; Naismith, Teresa V.; Snapp, Erik L.; Hanson, Phyllis I.

In: EMBO Journal, Vol. 30, No. 16, 17.08.2011, p. 3217-3231.

Research output: Contribution to journalArticle

Vander Heyden, AB, Naismith, TV, Snapp, EL & Hanson, PI 2011, 'Static retention of the lumenal monotopic membrane protein torsinA in the endoplasmic reticulum', EMBO Journal, vol. 30, no. 16, pp. 3217-3231. https://doi.org/10.1038/emboj.2011.233
Vander Heyden, Abigail B. ; Naismith, Teresa V. ; Snapp, Erik L. ; Hanson, Phyllis I. / Static retention of the lumenal monotopic membrane protein torsinA in the endoplasmic reticulum. In: EMBO Journal. 2011 ; Vol. 30, No. 16. pp. 3217-3231.
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