Dec 18, 2013

A mechanism for retromer endosomal coat complex assembly with cargo

Proceedings of the National Academy of Sciences of the United States of America
Megan S HarrisonChristopher G Burd

Abstract

Retromer is an evolutionarily conserved protein complex composed of the VPS26, VPS29, and VPS35 proteins that selects and packages cargo proteins into transport carriers that export cargo from the endosome. The mechanisms by which retromer is recruited to the endosome and captures cargo are unknown. We show that membrane recruitment of retromer is mediated by bivalent recognition of an effector of PI3K, SNX3, and the RAB7A GTPase, by the VPS35 retromer subunit. These bivalent interactions prime retromer to capture integral membrane cargo, which enhances membrane association of retromer and initiates cargo sorting. The role of RAB7A is severely impaired by a mutation, K157N, that causes Charcot-Marie-Tooth neuropathy 2B. The results elucidate minimal requirements for retromer assembly on the endosome membrane and reveal how PI3K and RAB signaling are coupled to initiate retromer-mediated cargo export.

  • References32
  • Citations41

Mentioned in this Paper

Saccharomyces cerevisiae Proteins
Charcot-Marie-Tooth Disease
Wall of Endosome
VPS35 protein, human
Rab7 protein, rat
Phosphatidylinositol 3-Kinases
CMT2B gene
VPS29 protein, human
Sorting Nexins
Plasma Protein Binding Capacity

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