Seminar

A mechanism for cargo recycling from endosomes

Aitor Hierro, PhD

Retromer is a multi-protein complex that recycles transmembrane cargo from endosomes to the trans-Golgi network and the plasma membrane. Defects in retromer alter the subcellular distribution of its transmembrane cargos and underlie some forms of Alzheimer’s disease and Parkinson’s disease. Although retromer was discovered over 15 years ago, the mechanisms for cargo recognition and recruitment to endosomes have remained elusive. We found a solution to this problem by determining the crystal structure of a four-component complex comprising the VPS26 and VPS35 subunits of retromer, the sorting nexin SNX3, and a recycling signal from the divalent cation transporter DMT1. The number of components involved and the occurrence of highly cooperative interactions among them explain why previous attempts at solving this structure failed. Our structure shows that the DMT1 signal binds to a hydrophobic pocket at the interface between VPS26 and SNX3. The most interesting aspect of this structure, however, is the fact that SNX3 induces a conformational change in VPS26 that exposes key residues of the signal-binding pocket while concomitantly mediating membrane recruitment via its phosphoinositide-binding site. The structure thus reveals a novel mechanism for cargo recognition coupled to membrane recruitment, and also suggests how the retromer coat is assembled on membrane tubules. These mechanisms are quite distinct from those involving the classical clathrin and coatomer coats in vesicular transport, and thus represent a new paradigm in protein sorting.