Structural insights into the retromer-SNX27 complex required for intracellular membrane trafficking — ASN Events
  1. Schedule
  2. Session Eight - Processing and Turnover
  3. Structural insights into the retromer-SNX27 complex required for intracellular membrane trafficking

Structural insights into the retromer-SNX27 complex required for intracellular membrane trafficking (#16)

Brett Collins 1 , Thomas Clairfeuille 1 , Matthew Gallon 2 , Peter Cullen 2
  1. Institute for Molecular Bioscience, St Lucia, QLD, Australia
  2. The Henry Wellcome Integrated Signalling Laboratories, School of Biochemistry, University of Bristol, Bristol, UK

The retromer-SNX27 complex is an essential mediator of intracellular membrane trafficking, controlling the recycling and homeostasis of cell-surface transmembrane proteins. Dysfunction and mutation of this protein assembly leads to neurodegenerative disorders including Parkinson’s and Alzheimer’s disease due to aberrant turnover of molecules such as the amyloid precursor protein, a-synuclein and synaptic glutamate receptors by lysosomal and autophagic degradation. Here we show how the retromer-SNX27 complex is assembled through direct association of the retromer VPS26 subunit and the PDZ domain of SNX27. The crystal structure of this complex reveals a novel PDZ domain interaction with an arrestin-fold related protein, and provides a molecular explanation for how transmembrane cargo proteins such as APP and glutamate receptors are engaged by this complex for tubulovesicular membrane trafficking. Cellular studies confirm the importance of this interaction in recycling of endocytosed receptors. Combined with previous structures this work is now providing a detailed understanding of retromer-SNX27, with implications for determining the impact of disease-causing mutations and the design of potential therapeutics that enhance the neuroprotective activity of this membrane transport pathway.

  1. M. Gallon†, T. Clairfeuille†, F. Steinberg, C. Mas, R. Ghai, R. Sessions, R. D. Teasdale, B. M. Collins# and P. J. Cullen# (2014) Structure of the SNX27:VPS26 complex reveals mechanistic details of endocytic recycling. Proc. Natl. Acad. Sci. USA. 111. E3604-E3613. †contributed equally. #Joint corresponding authors