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Papers In Press, published online ahead of print May 19, 2003
CBMB, NICHD, NIH, Bethesda, MD 20892
Corresponding Author: jmartina{at}mail.nih.gov
The Hermansky-Pudlak syndrome (HPS) is a genetic disorder characterized by defective lysosome-related organelles. HPS results from mutations in either one of six human genes named HPS1 to HPS6, most of which encode proteins of unknown function. Here we report that the human HPS1 and HPS4 proteins are part of a complex named BLOC-3 (for Biogenesis of Lysosome-related Organelles Complex 3). Co-immunoprecipitation experiments demonstrated that epitope-tagged and endogenous HPS1 and HPS4 proteins assemble with each other in vivo. The HPS1-HPS4 complex is predominantly cytosolic, with a small amount being peripherally associated with membranes. Size-exclusion chromatography and sedimentation velocity analyses of the cytosolic fraction indicate that HPS1 and HPS4 form a moderately asymmetric protein complex with a molecular mass of ~175 kDa. HPS4-deficient fibroblasts from light ear mice display normal distribution and trafficking of the lysosomal membrane protein, lamp-2, in contrast to fibroblasts from AP-3-deficient pearl (HPS2) mice, which exhibit increased trafficking of this lysosomal protein via the plasma membrane. Similarly, light ear fibroblasts display an apparently normal accumulation of Zn2+ in intracellular vesicles, unlike pearl fibroblasts, which exhibit a decreased intracellular Zn2+ storage. Taken together, these observations demonstrate that the HPS1 and HPS4 gene products are components of a cytosolic complex that is involved in the biogenesis of lysosomal-related organelles by a mechanism distinct from that operated by AP-3 complex.
J. Biol. Chem, 10.1074/jbc.M301294200
Submitted on February 5, 2003
Revised on May 15, 2003
Accepted on May 19, 2003
BLOC-3, a protein complex containing the Hermansky-Pudlak syndrome gene products HPS1 and HPS4
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