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The endosomal network is an interconnected membranous system that, by sorting cargoes from the plasma membrane and the biosynthetic pathway, performs an essential function in regulating numerous cellular processes. Network function can be defined by two fundamental events: (i), at the donor compartment cargo is selected and packaged into membrane-bound transport carriers; (ii), cargo-enriched carriers move towards and fuse with the correct recipient compartment. Unfortunately, at the molecular level we have a limited understanding of how such processes are orchestrated.
We have recently identified an endosomal complex that provides a unique opportunity to probe these events. Termed the SNX27-retromer, this sorts >250 transmembrane cargoes and has as its core SNX27. Cargo recognition is achieved through the SNX27 PDZ domain binding to PDZ-motif-containing cargoes and by binding the cargo-selective VPS26:VPS29:VPS35 trimer. SNX27 also associates, via its FERM-like domain, with a heterodimer of SNX1/SNX2 and SNX5/SNX6 that drives carrier formation by driving vesicle-to-tubule membrane re-modelling.
The PhD will combine the international recognised expertise of three groups: Cullen in functional analysis of endosomal sorting, Collinson in biophysical characterisation of multi-protein complexes and May in statistical analysis. Using biophysical techniques, including recombinant binding, crystallography and mutagenesis, we will build on preliminary data
and define the individual interactions that govern SNX27-retromer assembly. Molecular information will be translated by functional studies in mammalian cell culture and via Drosophila genetics, with transport being quantified by nanoscale automated particle tracking. Studying the SNX27-retromer ‘molecular machine’ will achieve new insight into the co-ordination between cargo selection and carrier formation.
Website: http://www.bris.ac.uk/biochemistry/cullen/index.html
Funding Notes:
Competitive funding for UK/EU students via the BBSRC SWDTP is currently available for the project
Assembly of endosomal sorting complexes: co-ordinating cargo selection with carrier formation. Prof Cullen, Prof Collinson, Dr May (School of Social and Community Medicine, University of Bristol)
For an opportunity to undertake a SWDTP funded project with this supervisor, please visit the SWDTP website:
http://www.bristol.ac.uk/swdtp
When applying online, please ensure you include "SWDTP Funded Project" in the "Research Details" section of the online form.
References:
Selected references highlighting the research questions and diverse techniques used within the laboratory:
Cullen PJ (2008) Endosomal sorting and signalling: an emerging role for sorting nexins. Nature Rev Mol Cell Biol 9, 574-582
Wassmer T, Attar N, Harterink M, van Weering JRT, Traer CJ, Oakley JD, Goud B, Stephens DJ, Verkade P, Korswagen HC and Cullen PJ (2009) The retromer coat complex co-ordinates endosomal sorting and dynein-mediated transport, with carrier recognition by the trans-Golgi network. Dev Cell 17, 110-122
van Weering JRT, Verkade P and Cullen PJ (2010) SNX-BAR proteins in phosphoinositide-mediated, tubular-based endosomal sorting. Sem Cell Dev Biol 21, 371-380
Harterink M, Port F, Lorenowicz MJ, McGough IJ, Sikankova M, Betist MC, van Weering JRT, van Heesbeen RGHP, Middelkoop T, Basler K, Cullen PJ* and Korswagen HC* (2011) A novel sorting nexin-3 dependent retromer pathway mediates retrograde transport of the Wnt sorting receptor Wntless and is required for Wnt secretion. Nature Cell Biol submitted. *joint senior authors