Sorting by the cytoplasmic domain of the amyloid precursor protein binding receptor SorLA.
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, platelet-derived growth factor-bb, and lipoprotein lipase, and via complex-formation with the amyloid precursor protein it downregulates generation of Alzheimer's disease-associated Abeta-peptide. The receptor is mainly located in vesicles, suggesting a function in protein sorting and transport. Here we examined SorLA's trafficking using full-length and chimeric receptors and find that its cytoplasmic tail mediates efficient Golgi body-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 mu1-chain-deficient cells established that the AP-1 adaptor complex is essential to SorLA's transport between Golgi membranes 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.
Nielsen
Morten S
MS
The MIND-Center, Department of Medical Biochemistry, Ole Worms Allé, Bldg 1170, University of Aarhus, 8000, Aarhus, Denmark.
Gustafsen
Camilla
C
Madsen
Peder
P
Nyengaard
Jens R
JR
Hermey
Guido
G
Bakke
Oddmund
O
Mari
Muriel
M
Schu
Peter
P
Pohlmann
Regina
R
Dennes
André
A
Petersen
Claus M
CM
D033942:Adaptor Proteins, Vesicular Transport; D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D011992:Endosomes / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000235:genetics / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D034622:RNA Interference; D015375:Receptors, Interleukin-2 / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism*; D020798:Two-Hybrid System Techniques; D000099183:Sortilin
D033942:Adaptor Proteins, Vesicular Transport; D016564:Amyloid beta-Protein Precursor; D026502:LDL-Receptor Related Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins; D000099183:Sortilin