title: Biogenesis of lysosome-related organelles complex 3 (BLOC-3): a complex containing the Hermansky-Pudlak syndrome (HPS) proteins HPS1 and HPS4.
abstract: Hermansky-Pudlak syndrome (HPS) defines a group of autosomal recessive disorders characterized by deficiencies in lysosome-related organelles such as melanosomes and platelet-dense granules. Several HPS genes encode proteins of unknown function including HPS1, HPS3, and HPS4. Here we have identified and characterized endogenous HPS3 and HPS4 proteins from HeLa cells. Both proteins were found in soluble and membrane-associated forms. Sedimentation-velocity and coimmunoprecipitation experiments revealed that HPS4 but not HPS3 associates with HPS1 in a complex, which we term biogenesis of lysosome-related organelles complex 3 (BLOC-3). Mutant fibroblasts deficient in either HPS1 or HPS4 displayed abnormal localization of lysosomes and late endosomes, which were less concentrated at the juxtanuclear region in mutant cells than in control fibroblasts. The coat-color phenotype of young homozygous double-mutant mice deficient in subunits of BLOC-3 (HPS1) and BLOC-1 (pallidin) was indistinguishable from that of BLOC-1 single mutants. Taken together, these observations suggest that HPS1 and HPS4 are components of a protein complex that regulates the intracellular localization of lysosomes and late endosomes and may function in a BLOC-1-dependent pathway for melanosome biogenesis.
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Ramin
authors.initials: R
authors.lastname: Nazarian
authors.forename: Juan M
authors.initials: JM
authors.lastname: Falcón-Pérez
authors.forename: Esteban C
authors.initials: EC
authors.lastname: Dell'Angelica
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors; D006200:Hair Color / Q000235:genetics; D006367:HeLa Cells; D022861:Hermanski-Pudlak Syndrome / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D037102:Lectins; D051907:Lysosomal Membrane Proteins; D008247:Lysosomes / Q000378:metabolism; D046911:Macromolecular Substances; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009154:Mutation; D015388:Organelles / Q000378:metabolism; D010641:Phenotype; D011506:Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012995:Solubility
chemical_list: D015703:Antigens, CD; C400284:BLOC1S6 protein, human; C513476:Bloc1s6 protein, mouse; D002352:Carrier Proteins; D020662:Guanine Nucleotide Exchange Factors; C102160:HPS1 protein, human; C432680:HPS3 protein, human; C451752:HPS4 protein, human; C491131:Hps1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D037102:Lectins; D051907:Lysosomal Membrane Proteins; D046911:Macromolecular Substances; D008565:Membrane Proteins; D011506:Proteins; D011993:Recombinant Fusion Proteins