MCB Accepts, published online ahead of print on 23 July 2007

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Mol. Cell. Biol. doi:10.1128/MCB.00815-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Sorting by the cytoplasmic domain of the amyloid precursor protein binding receptor SorLA

Morten S. Nielsen, Camilla Gustafsen, Peder Madsen, Jens R. Nyengaard, Guido Hermey, Oddmund Bakke, Muriel Mari, Peter Schu, Regina Pohlmann, André Dennes, and Claus M. Petersen^*

The MIND-center, Department of Medical Biochemistry and Stereology and Electron Microscopy Research Laboratory, University of Aarhus, 8000 Aarhus, Denmark; Department of Biology, Chemistry and Pharmacology, Free University of Berlin, Germany; Department of Molecular Cell Biology, University of Oslo, Norway; Department of Cell Biology, UMCU, Utrecht, The Netherlands; Department of Biochemistry and Molecular Cell Biology, University of Göttingen, Germany; Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, Germany

^* To whom correspondence should be addressed. Email: cmp{at}biokemi.au.dk.

SorLA/LR11 (250 kDa) is the largest and most composite member of the Vps10p-domain receptors, a family of type-1 proteins preferentially expressed in neuronal tissue. SorLA binds several ligands, including neurotensin, PDGF-bb and lipoprotein lipase, and via complex-formation with the amyloid precursor protein it down-regulates generation of Alzheimer's Disease-associated A-peptide. The receptor is mainly located in vesicles suggesting a function in protein sorting and transport. Here we have examined SorLA's trafficking using full-length and chimeric receptors and find that its cytoplasmic tail mediates efficient Golgi-endosome transport as well as AP-2 complex dependent endocytosis. Functional sorting sites were mapped to an acidic cluster-dileucine like motif and to a GGA binding site in the C-terminus. Experiments in permanently or transiently AP-1 µ1-chain deficient cells established that the AP-1 adaptor complex is essential to SorLA's transport between Golgi and endosomes. Our results further implicate the GGA proteins in SorLA trafficking and provide evidence that SNX1 and Vps35, as parts of the retromer complex or possibly in a separate context, are engaged in retraction of the receptor from endosomes.

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