SNARE chaperone Sly1 directly mediates close-range vesicle tethering

J Cell Biol. 2024 Jun 3;223(6):e202001032. doi: 10.1083/jcb.202001032. Epub 2024 Mar 13.

Abstract

The essential Golgi protein Sly1 is a member of the Sec1/mammalian Unc-18 (SM) family of SNARE chaperones. Sly1 was originally identified through remarkable gain-of-function alleles that bypass requirements for diverse vesicle tethering factors. Employing genetic analyses and chemically defined reconstitutions of ER-Golgi fusion, we discovered that a loop conserved among Sly1 family members is not only autoinhibitory but also acts as a positive effector. An amphipathic lipid packing sensor (ALPS)-like helix within the loop directly binds high-curvature membranes. Membrane binding is required for relief of Sly1 autoinhibition and also allows Sly1 to directly tether incoming vesicles to the Qa-SNARE on the target organelle. The SLY1-20 mutation bypasses requirements for diverse tethering factors but loses this ability if the tethering activity is impaired. We propose that long-range tethers, including Golgins and multisubunit tethering complexes, hand off vesicles to Sly1, which then tethers at close range to initiate trans-SNARE complex assembly and fusion in the early secretory pathway.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cytoplasmic Vesicles* / metabolism
  • Golgi Apparatus / genetics
  • Golgi Apparatus / metabolism
  • Mammals / metabolism
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism
  • Munc18 Proteins / analysis
  • Munc18 Proteins / genetics
  • Munc18 Proteins / metabolism
  • SNARE Proteins / genetics
  • SNARE Proteins / metabolism
  • Saccharomyces cerevisiae Proteins* / genetics
  • Saccharomyces cerevisiae Proteins* / metabolism
  • Saccharomyces cerevisiae* / cytology
  • Saccharomyces cerevisiae* / metabolism
  • Vesicular Transport Proteins / metabolism

Substances

  • Molecular Chaperones
  • Munc18 Proteins
  • Saccharomyces cerevisiae Proteins
  • SNARE Proteins
  • Vesicular Transport Proteins
  • SLY1 protein, S cerevisiae

Associated data

  • Dryad/10.5061/dryad.dr7sqvb5b