Article

The Hermansky-Pudlak Syndrome 3 (Cocoa) Protein Is a Component of the Biogenesis of Lysosome-related Organelles Complex-2 (BLOC-2)

Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 04/2004; 279(13):12935-42. DOI: 10.1074/jbc.M311311200
Source: PubMed

ABSTRACT

Hermansky-Pudlak syndrome (HPS) is a genetically heterogeneous inherited disease affecting vesicle trafficking among lysosome-related organelles. The Hps3, Hps5, and Hps6 genes are mutated in the cocoa, ruby-eye-2, and ruby-eye mouse pigment mutants, respectively, and their human orthologs are mutated in HPS3, HPS5, and HPS6 patients. These three genes encode novel proteins of unknown function. The phenotypes of Hps5/Hps5,Hps6/Hps6 and Hps3/Hps3,Hps6/Hps6 double mutant mice mimic, in coat and eye colors, in melanosome ultrastructure, and in levels of platelet dense granule serotonin, the corresponding phenotypes of single mutants. These facts suggest that the proteins encoded by these genes act within the same pathway or protein complex in vivo to regulate vesicle trafficking. Further, the Hps5 protein is destabilized within tissues of Hps3 and Hps6 mutants, as is the Hps6 protein within tissues of Hps3 and Hps5 mutants. Also, proteins encoded by these genes co-immunoprecipitate and occur in a complex of 350 kDa as determined by sucrose gradient and gel filtration analyses. Together, these results indicate that the Hps3, Hps5, and Hps6 proteins regulate vesicle trafficking to lysosome-related organelles at the physiological level as components of the BLOC-2 (biogenesis of lysosome-related organelles complex-2) protein complex and suggest that the pathogenesis and future therapies of HPS3, HPS5, and HPS6 patients are likely to be similar. Interaction of the Hps5 and Hps6 proteins within BLOC-2 is abolished by the three-amino acid deletion in the Hps6(ru) mutant allele, indicating that these three amino acids are important for normal BLOC-2 complex formation.

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    • "was purchased from Covance; and mouse anti–-adaptin (100/3) and mouse anti–-tubulin (GTU88) were purchased from Sigma-Aldrich. Polyclonal rabbit antisera to HPS6 (a gift from V. Faundez, Emory University, Atlanta, GA; Gautam et al., 2004), STX13 (Prekeris et al., 1998), ATP7A (Setty et al., 2008), TYR (Calvo et al., 1999), and the N terminus of mouse PMEL (used for the endocytosis assay; Theos et al., 2006 ) have been described previously. Rabbit antigiantin was obtained from Abcam (ab24586); rabbit anti-MYC (C-14) and anti-TYRP1 (H-90), used for immunoblotting, were obtained from Santa Cruz Biotechnology, Inc.; and rabbit anti-GFP was purchased from Invitrogen . "
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    ABSTRACT: Hermansky-Pudlak syndrome (HPS) is a group of disorders characterized by the malformation of lysosome-related organelles, such as pigment cell melanosomes. Three of nine characterized HPS subtypes result from mutations in subunits of BLOC-2, a protein complex with no known molecular function. In this paper, we exploit melanocytes from mouse HPS models to place BLOC-2 within a cargo transport pathway from recycling endosomal domains to maturing melanosomes. In BLOC-2-deficient melanocytes, the melanosomal protein TYRP1 was largely depleted from pigment granules and underwent accelerated recycling from endosomes to the plasma membrane and to the Golgi. By live-cell imaging, recycling endosomal tubules of wild-type melanocytes made frequent and prolonged contacts with maturing melanosomes; in contrast, tubules from BLOC-2-deficient cells were shorter in length and made fewer, more transient contacts with melanosomes. These results support a model in which BLOC-2 functions to direct recycling endosomal tubular transport intermediates to maturing melanosomes and thereby promote cargo delivery and optimal pigmentation. © 2015 Dennis et al.
    Full-text · Article · May 2015 · The Journal of Cell Biology
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    • "AP3B1 encodes the large b1 subunit of the adaptor-related protein complex-3 (AP-3), involved in protein trafficking to specialized endosomallysosomal organelles such as melanosomes (Dell'Angelica et al., 1998). HPS3, HPS5, and HPS6 form the BLOC-2 complex (biogenesis of lysosome-related organelles com- plex-2), also involved in lysosomal trafficking (Anikster et al., 2001; Gautam et al., 2004; Zhang et al., 2003). DTNBP1 and BLOC1S3 encode two subunits of the ubiquitously expressed BLOC-1 (biogenesis of lysosomerelated organelles complex-1) multisubunit protein complex , required for the normal biogenesis of melanosomes (Li et al., 2003; Morgan et al., 2006; Starcevic and Dell'Angelica, 2004). "
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    • "Electron microscopy studies of skin melanocytes in the various mouse mutants of HPS have yielded clues as to which genes are required for various stages of melanosome biogenesis; mutants of genes that act together have similar phenotypes [25], [26]. Yeast two hybrid and co-immunoprecipitation studies have confirmed the ultrastructural analyses in delineating the HPS proteins that interact in specific BLOC complexes, and showing that HPS3 (cocoa), HSP5 (ruby2J), and HPS6 (ruby-eyed) are components of BLOC-2 [22], [27], [28]. HPS3 (cocoa), a member of the BLOC-2 complex, binds to clathrin-coated vesicles in the cytoplasm of human skin melanocytes [29]. "
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