Self-assembly of VPS41 promotes sorting required for biogenesis of the regulated secretory pathway

Dev Cell. 2013 Nov 25;27(4):425-37. doi: 10.1016/j.devcel.2013.10.007. Epub 2013 Nov 7.

Abstract

The regulated release of polypeptides has a central role in physiology, behavior, and development, but the mechanisms responsible for production of the large dense core vesicles (LDCVs) capable of regulated release have remained poorly understood. Recent work has implicated cytosolic adaptor protein AP-3 in the recruitment of LDCV membrane proteins that confer regulated release. However, AP-3 in mammals has been considered to function in the endolysosomal pathway and in the biosynthetic pathway only in yeast. We now find that the mammalian homolog of yeast VPS41, a member of the homotypic fusion and vacuole protein sorting (HOPS) complex that delivers biosynthetic cargo to the endocytic pathway in yeast, promotes LDCV formation through a common mechanism with AP-3, indicating a conserved role for these proteins in the biosynthetic pathway. VPS41 also self-assembles into a lattice, suggesting that it acts as a coat protein for AP-3 in formation of the regulated secretory pathway.

Publication types

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

MeSH terms

  • Animals
  • COS Cells
  • Chlorocebus aethiops
  • DNA-(Apurinic or Apyrimidinic Site) Lyase
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Drosophila Proteins
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / metabolism*
  • Endosomes / metabolism
  • Exocytosis / physiology*
  • Humans
  • Membrane Fusion
  • Membrane Proteins / metabolism
  • Organelle Biogenesis*
  • PC12 Cells
  • Protein Transport
  • Rats
  • Secretory Pathway / physiology*
  • Secretory Vesicles / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Vesicular Monoamine Transport Proteins / metabolism
  • Vesicular Transport Proteins / genetics
  • Vesicular Transport Proteins / metabolism*

Substances

  • DNA-Binding Proteins
  • Drosophila Proteins
  • Membrane Proteins
  • Ribosomal protein P0, Drosophila
  • Transcription Factors
  • VPS41 protein, human
  • Vesicular Monoamine Transport Proteins
  • Vesicular Transport Proteins
  • enhancer-binding protein AP-3
  • DNA-(Apurinic or Apyrimidinic Site) Lyase