期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 284, 期 3, 页码 1790-1802出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M805991200
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资金
- National Institutes of Health [NS42599, GM 077569]
- MRC [G120/952] Funding Source: UKRI
- Medical Research Council [G120/952] Funding Source: researchfish
The Hermansky-Pudlak syndrome is a disorder affecting endosome sorting. Disease is triggered by defects in any of 15 mouse gene products, which are part of five distinct cytosolic molecular complexes: AP-3, homotypic fusion and vacuole protein sorting, and BLOC-1, -2, and -3. To identify molecular associations of these complexes, we used in vivo cross-linking followed by purification of cross-linked AP-3 complexes and mass spectrometric identification of associated proteins. AP-3 was co-isolated with BLOC-1, BLOC-2, and homotypic fusion and vacuole protein sorting complex subunits; clathrin; and phosphatidylinositol-4- kinase type II alpha ( PI4KII alpha). We previously reported that this membrane-anchored enzyme is a regulator of AP-3 recruitment to membranes and a cargo of AP-3 (Craige, B., Salazar, G., and Faundez, V. (2008) Mol. Biol. Cell 19, 1415 1426). Using cells deficient in different Hermansky-Pudlak syndrome complexes, we identified that BLOC-1, but not BLOC-2 or BLOC-3, deficiencies affect PI4KII alpha inclusion into AP-3 complexes. BLOC-1, PI4KII alpha, and AP-3 belong to a tripartite complex, and down-regulation of either PI4KII alpha, BLOC-1, or AP-3 complexes led to similar LAMP1 phenotypes. Our analysis indicates that BLOC-1 complex modulates the association of PI4KII alpha with AP-3. These results suggest that AP-3 and BLOC-1 act, either in concert or sequentially, to specify sorting of PI4KII alpha along the endocytic route.
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