Biogenesis of Melanosomes

Boissy, Raymond E.; Huizing, Marjan; Gahl, William A.

doi:10.1002/9780470987100.ch7

Cited by 21 publications

(19 citation statements)

References 201 publications

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“…1A) and, more importantly, by applying the immunoprecipitation-recapture procedure to whole cell extracts from HPS-1 patient fibroblasts (Fig. 1B), which had been predicted to express little or no HPS1p due to enhanced degradation of the HPS1 mRNA (9,29). The electrophoretic mobility of endogenous HPS1p was consistent with the molecular mass predicted for the product of the major HPS1 transcript (9).…”

Section: Discussionsupporting

confidence: 59%

“…In addition, virtually no protein bands were detected when the immunoprecipitation-recapture procedure was performed on fibroblasts from two unrelated HPS-1 patients homozygous for a 16-bp duplication in HPS1 (Fig. 1B); this mutation had been shown to affect the stability of the HPS1 mRNA (9,29) and predicted to result in very low cellular levels of HPS1p. Fibroblasts from an AP-3 ␤3A-deficient HPS-2 patient were found to express normal levels of HPS1p (Fig.…”

Section: Ref 28) Hela Cells Metabolically Labeled With [mentioning

confidence: 99%

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Molecular Characterization of the Protein Encoded by the Hermansky-Pudlak Syndrome Type 1 Gene

Dell’Angelica

Aguilar

Wolins

et al. 2000

Journal of Biological Chemistry

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Hermansky-Pudlak syndrome (HPS) comprises a group of genetic disorders characterized by defective lysosome-related organelles. The most common form of HPS (HPS type 1) is caused by mutations in a gene encoding a protein with no homology to any other known protein. Here we report the identification and biochemical characterization of this gene product, termed HPS1p. Endogenous HPS1p was detected in a wide variety of human cell lines and exhibited an electrophoretic mobility corresponding to a protein of ϳ80 kDa. In contrast to previous theoretical analysis predicting that HPS1p is an integral membrane protein, we found that this protein was predominantly cytosolic, with a small amount being peripherally associated with membranes. The sedimentation coefficient of the soluble form of HPS1p was ϳ6 S as inferred from ultracentrifugation on sucrose gradients. HPS1p-deficient cells derived from patients with HPS type 1 displayed normal distribution and trafficking of the lysosomal membrane proteins, CD63 and Lamp-1. This was in contrast to cells from HPS type 2 patients, having mutations in the ␤3A subunit of the AP-3 adaptor complex, which exhibited increased routing of these lysosomal proteins through the plasma membrane. Similar analyses performed on fibroblasts from 10 different mouse models of HPS revealed that only the AP-3 mutants pearl and mocha display increased trafficking of Lamp-1 through the plasma membrane. Taken together, these observations suggest that the product of the HPS1 gene is a cytosolic protein capable of associating with membranes and involved in the biogenesis and/or function of lysosome-related organelles by a mechanism distinct from that dependent on the AP-3 complex.

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Section: Discussionsupporting

confidence: 59%

Section: Ref 28) Hela Cells Metabolically Labeled With [mentioning

confidence: 99%

Molecular Characterization of the Protein Encoded by the Hermansky-Pudlak Syndrome Type 1 Gene

Dell’Angelica

Aguilar

Wolins

et al. 2000

Journal of Biological Chemistry

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“…The HPS1 protein may also function in the trafficking of melanocyte-specific proteins from the TGN to preformed premelanosomes. HPS-1 melanocytes display a large granular pattern of expression for the pigment-forming proteins tyrosinase related protein-1 (TRP-1) and granulophysin, consistent with the large membrane complexes observed ultrastructurally [76]. In the absence of HPS1 proteins, melanogenic proteins apparently fail to colocalize with melanosomes, and enter large granules by default.…”

Section: The Hps1 Gene Productmentioning

confidence: 75%

Disorders of Vesicles of Lysosomal Lineage: The Hermansky- Pudlak Syndromes

Huizing

Gahl²

2002

CMM

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108

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Hermansky-Pudlak syndrome (HPS) has evolved into a group of genetically distinct disorders characterized by oculocutaneous albinism, a storage pool deficiency, and impaired formation or trafficking of intracellular vesicles. HPS-1 results from mutations in the HPS1 gene and affects approximately 400 individuals in northwest Puerto Rico due to a 16-bp duplication in exon 15. Another 13 mutations have been reported in non-Puerto Ricans. HPS1 codes for a 79.3 kDa cytoplasmic protein of unknown function. HPS-1 patients typically develop fatal pulmonary fibrosis in their fourth decade. HPS-2 is caused by mutations in ADTB3A, which codes for the beta3A subunit of the adaptor protein-3 complex, AP3. This coat protein complex has been localized to the TGN as well as to a peripheral endosomal compartment. Evidence indicates that AP3 plays a role in the stepwise process of vesicular trafficking which leads to formation of the melanosomal, platelet dense body and lysosomal compartments. All three known HPS-2 patients had childhood neutropenia and infections. HPS-3 results from mutations in HPS3 and affects central Puerto Ricans homozygous for a 3904-bp deletion removing exon 1. At least 8 non-Puerto Rican patients have other HPS3 mutations, including an IVS5+1G->A splicing mutation in five Ashkenazi Jewish patients. HPS3 codes for a 113.7 kDa protein of unknown function. HPS-3 manifests with mild hypopigmentation and bleeding. All types of HPS are diagnosed by whole mount electron microscopic demonstration of absent platelet dense bodies, and molecular diagnoses are available for the Puerto Rican HPS1 and HPS3 founder mutations. Mouse and Drosophila models provide candidates for new genes causing HPS in humans. These genes will reveal the pathways by which specialized vesicles of lysosomal lineage arise within cells.

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“…For instance, melanosomes and lysosomes contain many of the same structural proteins (e.g. LAMP, acidic hydrolases, vacuolar-type proton pumps (47,74,75)), and both are affected in several genetic disorders, such as the Chediak-Higashi and Hermansky-Pudlak syndromes (76,77). The catalytic domains of TYR and other enzymes involved in melanogenesis are located within the lumen of the melanosome, and it follows that their activity is likely to be dependent upon the intramelanosomal environment, including the pH (19).…”

Section: Discussionmentioning

confidence: 99%

Regulation of Tyrosinase Processing and Trafficking by Organellar pH and by Proteasome Activity

Watabe

Valencia

Yasumoto

et al. 2004

Journal of Biological Chemistry

122

105

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Pigmentation of the hair, skin, and eyes of mammals results from a number of melanocyte-specific proteins that are required for the biosynthesis of melanin. Those proteins comprise the structural and enzymatic components of melanosomes, the membrane-bound organelles in which melanin is synthesized and deposited. Tyrosinase (TYR) is absolutely required for melanogenesis, but other melanosomal proteins, such as TYRP1, DCT, and gp100, also play important roles in regulating mammalian pigmentation. However, pigmentation does not always correlate with the expression of TYR mRNA/protein, and thus its function is also regulated at the post-translational level. Thus, TYR does not necessarily exist in a catalytically active state, and its post-translational activation could be an important control point for regulating melanin synthesis. In this study, we used a multidisciplinary approach to examine the processing and sorting of TYR through the endoplasmic reticulum (ER), Golgi apparatus, coated vesicles, endosomes and early melanosomes because those organelles hold the key to understanding the trafficking of TYR to melanosomes and thus the regulation of melanogenesis. In pigmented cells, TYR is trafficked through those organelles rapidly, but in amelanotic cells, TYR is retained within the ER and is eventually degraded by proteasomes. We now show that TYR can be released from the ER in the presence of protonophore or proton pump inhibitors which increase the pH of intracellular organelles, after which TYR is transported correctly to the Golgi, and then to melanosomes via the endosomal sorting system. The expression of TYRP1, which facilitates TYR processing in the ER, is down-regulated in the amelanotic cells; this is analogous to a hypopigmentary disease known as oculocutaneous albinism type 3 and further impairs melanin production. The sum of these results shows that organellar pH, proteasome activity, and down-regulation of TYRP1 expression all contribute to the lack of pigmentation in TYRpositive amelanotic melanoma cells.

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Biogenesis of Melanosomes

Cited by 21 publications

References 201 publications

Molecular Characterization of the Protein Encoded by the Hermansky-Pudlak Syndrome Type 1 Gene

Molecular Characterization of the Protein Encoded by the Hermansky-Pudlak Syndrome Type 1 Gene

Disorders of Vesicles of Lysosomal Lineage: The Hermansky- Pudlak Syndromes

Regulation of Tyrosinase Processing and Trafficking by Organellar pH and by Proteasome Activity

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