Structural Mechanism for Cargo Recognition by the Retromer Complex

Cell. 2016 Dec 1;167(6):1623-1635.e14. doi: 10.1016/j.cell.2016.10.056. Epub 2016 Nov 23.


Retromer is a multi-protein complex that recycles transmembrane cargo from endosomes to the trans-Golgi network and the plasma membrane. Defects in retromer impair various cellular processes 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. Here, we present an X-ray crystallographic analysis 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-II. This analysis identifies a binding site for canonical recycling signals at the interface between VPS26 and SNX3. In addition, the structure highlights a network of cooperative interactions among the VPS subunits, SNX3, and cargo that couple signal-recognition to membrane recruitment.

Keywords: cargo recognition; endocytic recycling; endosomes; membrane recruitment; membrane tubules; protein coats; retrograde transport; retromer; sorting nexins; sorting signals.

MeSH terms

  • Amino Acid Sequence
  • Cation Transport Proteins / chemistry*
  • Cation Transport Proteins / metabolism
  • Crystallography, X-Ray
  • Humans
  • Models, Molecular
  • Multiprotein Complexes / chemistry*
  • Protein Isoforms / chemistry
  • Protein Isoforms / metabolism
  • Scattering, Small Angle
  • Sorting Nexins / chemistry*
  • Sorting Nexins / metabolism
  • Vesicular Transport Proteins / chemistry*
  • Vesicular Transport Proteins / metabolism


  • Cation Transport Proteins
  • Multiprotein Complexes
  • Protein Isoforms
  • SNX3 protein, human
  • Sorting Nexins
  • VPS26A protein, human
  • VPS35 protein, human
  • Vesicular Transport Proteins
  • solute carrier family 11- (proton-coupled divalent metal ion transporters), member 2