title: Recruitment of the endosomal WASH complex is mediated by the extended 'tail' of Fam21 binding to the retromer protein Vps35.
abstract: The retromer complex is a conserved endosomal protein sorting complex that sorts membrane proteins into nascent endosomal tubules. The recognition of membrane proteins is mediated by the cargo-selective retromer complex, a stable trimer of the Vps35 (vacuolar protein sorting 35), Vps29 and Vps26 proteins. We have recently reported that the cargo-selective retromer complex associates with the WASH (Wiskott-Aldrich syndrome homologue) complex, a multimeric protein complex that regulates tubule dynamics at endosomes. In the present study, we show that the retromer-WASH complex interaction occurs through the long unstructured 'tail' domain of the WASH complex-Fam21 protein binding to Vps35, an interaction that is necessary and sufficient to target the WASH complex to endosomes. The Fam21-tail also binds to FKBP15 (FK506-binding protein 15), a protein associated with ulcerative colitis, to mediate the membrane association of FKBP15. Elevated Fam21-tail expression inhibits the association of the WASH complex with retromer, resulting in increased cytoplasmic WASH complex. Additionally, overexpression of the Fam21-tail results in cell-spreading defects, implicating the activity of the WASH complex in regulating the mobilization of membrane into the endosome-to-cell surface pathway.
authors: Cambridge Institute for Medical Research/Department of Clinical Biochemistry, University of Cambridge, Addenbrookes Hospital, Cambridge CB2 0XY, UK.
authors: Michael E
authors: ME
authors: Harbour
authors: Sophia Y
authors: SY
authors: Breusegem
authors: Matthew N J
authors: MN
authors: Seaman
mesh_terms: D011992:Endosomes / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D008840:Microfilament Proteins / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology*; D011506:Proteins / Q000378:metabolism*; D022021:Tacrolimus Binding Proteins; D033921:Vesicular Transport Proteins / Q000378:metabolism*; D051316:Wiskott-Aldrich Syndrome Protein / Q000378:metabolism*; D051300:Wiskott-Aldrich Syndrome Protein Family
chemical_list: C540489:FKBP15 protein, human; D008565:Membrane Proteins; D008840:Microfilament Proteins; D011506:Proteins; C419573:VPS35 protein, human; D033921:Vesicular Transport Proteins; C549919:WASH protein, human; C517003:WASHC5 protein, human; D051316:Wiskott-Aldrich Syndrome Protein; D051300:Wiskott-Aldrich Syndrome Protein Family; D022021:Tacrolimus Binding Proteins