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


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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Available from: Rashi Gautam, Oct 05, 2015
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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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    ABSTRACT: Albinism is a rare genetic condition globally characterized by a number of specific deficits in the visual system, resulting in poor vision, in association with a variable hypopigmentation phenotype. This lack or reduction of pigment might affect the eyes, skin and hair (oculocutaneous albinism, OCA), or only the eyes (ocular albinism, OA). In addition, there are several syndromic forms of albinism (e.g., Hermansky-Pudlak and Chediak-Higashi syndromes, HPS and CHS, respectively) in which the described hypopigmented and visual phenotypes coexist with more severe pathological alterations. Recently, a locus has been mapped to the 4q24 human chromosomal region and thus represents an additional genetic cause of OCA, termed OCA5, while the gene is eventually identified. In addition, two new genes have been identified as causing OCA when mutated: SLC24A5 and C10orf11, and hence designated as OCA6 and OCA7, respectively. This consensus review, involving all laboratories that have reported these new genes, aims to update and agree upon the current gene nomenclature and types of albinism, while providing additional insights from the function of these new genes in pigment cells. This article is protected by copyright. All rights reserved.
    Pigment Cell & Melanoma Research 09/2013; 27(1). DOI:10.1111/pcmr.12167 · 4.62 Impact Factor
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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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    ABSTRACT: Humans with Hermansky-Pudlak Syndrome (HPS) or ocular albinism (OA1) display abnormal aspects of organelle biogenesis. The multigenic disorder HPS displays broad defects in biogenesis of lysosome-related organelles including melanosomes, platelet dense granules, and lysosomes. A phenotype of ocular pigmentation in OA1 is a smaller number of macromelanosomes, in contrast to HPS, where in many cases the melanosomes are smaller than normal. In these studies we define the role of the Mreg(dsu) gene, which suppresses the coat color dilution of Myo5a, melanophilin, and Rab27a mutant mice in maintaining melanosome size and distribution. We show that the product of the Mreg(dsu) locus, melanoregulin (MREG), interacts both with members of the HPS BLOC-2 complex and with Oa1 in regulating melanosome size. Loss of MREG function facilitates increase in the size of micromelanosomes in the choroid of the HPS BLOC-2 mutants ruby, ruby2, and cocoa, while a transgenic mouse overexpressing melanoregulin corrects the size of retinal pigment epithelium (RPE) macromelanosomes in Oa1(ko/ko) mice. Collectively, these results suggest that MREG levels regulate pigment incorporation into melanosomes. Immunohistochemical analysis localizes melanoregulin not to melanosomes, but to small vesicles in the cytoplasm of the RPE, consistent with a role for this protein in regulating membrane interactions during melanosome biogenesis. These results provide the first link between the BLOC pathway and Oa1 in melanosome biogenesis, thus supporting the hypothesis that intracellular G-protein coupled receptors may be involved in the biogenesis of other organelles. Furthermore these studies provide the foundation for therapeutic approaches to correct the pigment defects in the RPE of HPS and OA1.
    PLoS ONE 09/2012; 7(9):e42446. DOI:10.1371/journal.pone.0042446 · 3.23 Impact Factor
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    • "In a few HPS cases in which the molecular consequences of disease-causing mutations have been studied, the mutations were found not only to affect the protein encoded by the mutant gene but also to lead to secondary destabilization and degradation of the corresponding protein complex [9]; a similar phenomenon was observed in mouse strains carrying mutations in the orthologs of each of the genes associated with HPS in humans [10] [12] [14] [15] [16] [17]. This has led to the notion that the different types of HPS could be classified into clinically relevant groups depending upon the affected protein complex [1]. "
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    ABSTRACT: Hermansky-Pudlak syndrome (HPS) comprises a constellation of human autosomal recessive disorders characterized by albinism and platelet storage pool deficiency. At least eight types of HPS have been defined based on the identity of the mutated gene. These genes encode components of four ubiquitously expressed protein complexes, named Adaptor Protein (AP)-3 and Biogenesis of Lysosome-related Organelles Complex (BLOC)-1 through -3. In patients of Puerto Rican origin, the molecular diagnosis can be based on analysis of two founder mutations. On the other hand, identification of the HPS type in other patients relies on the sequencing of all candidate genes. In this work, we have developed a biochemical assay to minimize the number of candidate genes to be sequenced per patient. The assay consists of immunoblotting analysis of extracts prepared from skin fibroblasts, using antibodies to one subunit per protein complex. The assay allowed us to determine which complex was defective in each of a group of HPS patients with unknown genetic lesions, thus subsequent sequencing was limited to genes encoding the corresponding subunits. Because no mutations within the two genes encoding BLOC-3 subunits could be found in two patients displaying reduced BLOC-3 levels, the possible existence of additional subunits was considered. Through size-exclusion chromatography and sedimentation velocity analysis, the native molecular mass of BLOC-3 was estimated to be 140+/-30 kDa, a value most consistent with the idea that BLOC-3 is a HPS1HPS4 heterodimer (approximately 156 kDa) albeit not inconsistent with the putative existence of a relatively small third subunit.
    Molecular Genetics and Metabolism 03/2008; 93(2):134-44. DOI:10.1016/j.ymgme.2007.09.001 · 2.63 Impact Factor
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