Phosphorylation of a membrane curvature-sensing motif switches function of the HOPS subunit Vps41 in membrane tethering

Margarita Cabrera, Lars Langemeyer, Muriel Mari, Ralf Rethmeier, Ioan Orban, Angela Perz, Cornelia Bröcker, Janice Griffith, Daniel Klose, Heinz-Jürgen Steinhoff, Fulvio Reggiori, Siegfried Engelbrecht-Vandré, Christian Ungermann

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Tethering factors are organelle-specific multisubunit protein complexes that identify, along with Rab guanosine triphosphatases, transport vesicles and trigger their SNARE-mediated fusion of specific transport vesicles with the target membranes. Little is known about how tethering factors discriminate between different trafficking pathways, which may converge at the same organelle. In this paper, we describe a phosphorylation-based switch mechanism, which allows the homotypic vacuole fusion protein sorting effector subunit Vps41 to operate in two distinct fusion events, namely endosome-vacuole and AP-3 vesicle-vacuole fusion. Vps41 contains an amphipathic lipid-packing sensor (ALPS) motif, which recognizes highly curved membranes. At endosomes, this motif is inserted into the lipid bilayer and masks the binding motif for the δ subunit of the AP-3 complex, Apl5, without affecting the Vps41 function in endosome-vacuole fusion. At the much less curved vacuole, the ALPS motif becomes available for phosphorylation by the resident casein kinase Yck3. As a result, the Apl5-binding site is exposed and allows AP-3 vesicles to bind to Vps41, followed by specific fusion with the vacuolar membrane. This multifunctional tethering factor thus discriminates between trafficking routes by switching from a curvature-sensing to a coat recognition mode upon phosphorylation.

Original languageEnglish
Pages (from-to)845-859
Number of pages15
JournalJournal of Cell Biology
Issue number4
Publication statusPublished - 15-Nov-2010
Externally publishedYes


  • Amino Acid Motifs
  • Animals
  • Casein Kinase I
  • Cell Membrane
  • Endosomes
  • Molecular Sequence Data
  • Multiprotein Complexes
  • Phosphorylation
  • Recombinant Fusion Proteins
  • Saccharomyces cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Sequence Alignment
  • Vacuoles
  • Vesicular Transport Proteins
  • rab GTP-Binding Proteins

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