Dynamics and retention of misfolded proteins in native ER membranes

Sarah Nehls, Erik L. Snapp, Nelson B. Cole, Kristien J.M. Zaal, Anne K. Kenworthy, Theresa H. Roberts, Jan Ellenberg, John F. Presley, Eric Siggia, Jennifer Lippincott-Schwartz

Research output: Contribution to journalArticle

204 Scopus citations

Abstract

When co-translationally inserted into endoplasmic reticulum (ER) membranes, newly synthesized proteins encounter the lumenal environment of the ER, which contains chaperone proteins that facilitate the folding reactions necessary for protein oligomerization, maturation and export from the ER. Here we show, using a temperature-sensitive variant of vesicular stomatitis virus G protein tagged with green fluorescent protein (VSVG-GFP), and fluorescence recovery after photobleaching (FRAP), the dynamics of association of folded and misfolded VSVG complexes with ER chaperones. We also investigate the potential mechanisms underlying protein retention in the ER. Misfolded VSVG-GFP complexes at 40 °C are highly mobile in ER membranes and do not reside in post-ER compartments, indicating that they are not retained in the ER by immobilization or retrieval mechanisms. These complexes are immobilized in ATP-depleted or tunicamycin-treated cells, in which VSVG-chaperone interactions are no longer dynamic. These results provide insight into the mechanisms of protein retention in the ER and the dynamics of protein-folding complexes in native ER membranes.

Original languageEnglish (US)
Pages (from-to)288-295
Number of pages8
JournalNature Cell Biology
Volume2
Issue number5
DOIs
StatePublished - Oct 30 2000

ASJC Scopus subject areas

  • Cell Biology

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    Nehls, S., Snapp, E. L., Cole, N. B., Zaal, K. J. M., Kenworthy, A. K., Roberts, T. H., Ellenberg, J., Presley, J. F., Siggia, E., & Lippincott-Schwartz, J. (2000). Dynamics and retention of misfolded proteins in native ER membranes. Nature Cell Biology, 2(5), 288-295. https://doi.org/10.1038/35010558