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Vol. 16, Issue 9, 3951-3962, September 2005

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Structure-based Functional Analysis Reveals a Role for the SM Protein Sly1p in Retrograde Transport to the Endoplasmic Reticulum

Max Planck Institute for Biophysical Chemistry, Department of Molecular Genetics, 37077 Göttingen, Germany

Submitted February 10, 2005; Revised May 26, 2005; Accepted June 8, 2005
Monitoring Editor: Akihiko Nakano

Sec1p/Munc18 (SM) proteins are essential for membrane fusion events in eukaryotic cells. Here we describe a systematic, structure-based mutational analysis of the yeast SM protein Sly1p, which was previously shown to function in anterograde endoplasmic reticulum (ER)-to-Golgi and intra-Golgi protein transport. Five new temperature-sensitive (ts) mutants, each carrying a single amino acid substitution in Sly1p, were identified. Unexpectedly, not all of the ts mutants exhibited striking anterograde ER-to-Golgi transport defects. For example, in cells of the novel sly1-5 mutant, transport of newly synthesized lysosomal and secreted proteins was still efficient, but the ER-resident Kar2p/BiP was missorted to the outside of the cell, and two proteins, Sed5p and Rer1p, which normally shuttle between the Golgi and the ER, failed to relocate to the ER. We also discovered that in vivo, Sly1p was associated with a SNARE complex formed on the ER, and that in vitro, the SM protein directly interacted with the ER-localized nonsyntaxin SNAREs Use1p/Slt1p and Sec20p. Furthermore, several conditional mutants defective in Golgi-to-ER transport were synthetically lethal with sly1-5. Together, these results indicate a previously unrecognized function of Sly1p in retrograde transport to the endoplasmic reticulum.

Abbreviations used: ER, endoplasmic reticulum; SM, Sec1/Munc18 proteins; SNARE, soluble N-ethylmaleimide-sensitive fusion (NSF)-attachment protein receptors; CPY, carboxypeptidase; ALP, alkaline phosphatase.

Address correspondence to: Renwang Peng (rpeng{at}gwdg.de) or Dieter Gallwitz (Dieter.Gallwitz{at}mpi-bpc.mpg.de).

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