Abstract
BackgroundHermansky-Pudlak syndrome (HPS) is a disorder of lysosome-related organelle biogenesis characterized by oculocutaneous albinism and prolonged bleeding. These clinical findings reflect defects in the formation of melanosomes in melanocytes and dense bodies in platelets. HPS type-3 (HPS-3) results from mutations in the HPS3 gene, which encodes a 1004 amino acid protein of unknown function that contains a predicted clathrin-binding motif (LLDFE) at residues 172–176.ResultsClathrin was co-immunoprecipitated by HPS3 antibodies from normal but not HPS3 null melanocytes. Normal melanocytes expressing a GFP-HPS3 fusion protein demonstrated partial co-localization of GFP-HPS3 with clathrin following a 20°C temperature block. GFP-HPS3 in which the predicted clathrin-binding domain of HPS3 was mutated (GFP-HPS3-delCBD) did not co-localize with clathrin under the same conditions. Immunoelectron microscopy of normal melanocytes expressing GFP-HPS3 showed co-localization of GFP-HPS3 with clathrin, predominantly on small vesicles in the perinuclear region. In contrast, GFP-HPS3-delCBD did not co-localize with clathrin and exhibited a largely cytoplasmic distribution.ConclusionHPS3 associates with clathrin, predominantly on small clathrin-containing vesicles in the perinuclear region. This association most likely occurs directly via a functional clathrin-binding domain in HPS3. These results suggest a role for HPS3 and its protein complex, BLOC-2, in vesicle formation and trafficking.
Highlights
Hermansky-Pudlak syndrome (HPS) is a disorder of lysosome-related organelle biogenesis characterized by oculocutaneous albinism and prolonged bleeding
Seven genes have been identified as causes of human HPS subtypes (HPS-1 through HPS-7), and other genes identified in mouse models of HPS may cause HPS in humans [4,11]
In an attempt to understand the function of HPS gene products, we focused on HPS3, a unique protein with a predicted clathrin-binding domain
Summary
Hermansky-Pudlak syndrome (HPS) is a disorder of lysosome-related organelle biogenesis characterized by oculocutaneous albinism and prolonged bleeding. These clinical findings reflect defects in the formation of melanosomes in melanocytes and dense bodies in platelets. Hermansky-Pudlak syndrome (HPS [MIM: 203300]) is an autosomal recessive disorder of vesicle biogenesis resulting in the dysfunction of lysosome-related organelles such as melanosomes and platelet dense bodies [1,2,3,4]. AP3B1 codes for the β3A subunit of adaptor complex-3 (AP-3), a coat protein that is involved in sorting transmembrane proteins to lysosomes and lysosome-related organelles [12,13,14,15] This recognized function of AP-3 supports the paradigm that all types of HPS result from abnormal vesicle formation and/ or trafficking
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