title: The molecular basis for the endocytosis of small R-SNAREs by the clathrin adaptor CALM.
abstract: SNAREs provide a large part of the specificity and energy needed for membrane fusion and, to do so, must be localized to their correct membranes. Here, we show that the R-SNAREs VAMP8, VAMP3, and VAMP2, which cycle between the plasma membrane and endosomes, bind directly to the ubiquitously expressed, PtdIns4,5P(2)-binding, endocytic clathrin adaptor CALM/PICALM. X-ray crystallography shows that the N-terminal halves of their SNARE motifs bind the CALM(ANTH) domain as helices in a manner that mimics SNARE complex formation. Mutation of residues in the CALM:SNARE interface inhibits binding in vitro and prevents R-SNARE endocytosis in vivo. Thus, CALM:R-SNARE interactions ensure that R-SNAREs, required for the fusion of endocytic clathrin-coated vesicles with endosomes and also for subsequent postendosomal trafficking, are sorted into endocytic vesicles. CALM's role in directing the endocytosis of small R-SNAREs may provide insight into the association of CALM/PICALM mutations with growth retardation, cognitive defects, and Alzheimer's disease.
authors: Cambridge Institute for Medical Research and Department of Clinical Biochemistry, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK.
authors: Sharon E
authors: SE
authors: Miller
authors: Daniela A
authors: DA
authors: Sahlender
authors: Stephen C
authors: SC
authors: Graham
authors: Stefan
authors: S
authors: Höning
authors: Margaret S
authors: MS
authors: Robinson
authors: Andrew A
authors: AA
authors: Peden
authors: David J
authors: DJ
authors: Owen
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D018360:Crystallography, X-Ray; D004705:Endocytosis; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D034041:Monomeric Clathrin Assembly Proteins / Q000378:metabolism*; D050683:R-SNARE Proteins / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D050600:SNARE Proteins / Q000737:chemistry* / Q000378:metabolism; D022161:Transport Vesicles / Q000378:metabolism
chemical_list: D034041:Monomeric Clathrin Assembly Proteins; D050683:R-SNARE Proteins; D050600:SNARE Proteins