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Divalent interaction between HPS1 and HPS4 to form the Biogenesis of Lysosome‐related Organelles 3 (BLOC‐3)
Author(s) -
CarmonaRivera Carmelo,
Bonifacino Juan S,
Gahl William A,
Cadilla Carmen L
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.522.3
Subject(s) - lysosome , pulmonary fibrosis , biogenesis , hermansky–pudlak syndrome , lipofuscin , organelle , biology , organelle biogenesis , phenotype , gene , pathology , genetics , medicine , fibrosis , biochemistry , enzyme
Hermansky‐Pudlak Syndrome (HPS) [MIM#203300] is a rare autosomal recessive disorder characterized by oculocutaneous albinism, a bleeding tendency, and sporadic pulmonary fibrosis, granulomatous colitis or infections. HPS is a heterogeneous disorder; eight HPS‐causing genes have been identified in humans. HPS type 1 is the most severe subtype with a prevalence of ~1/1800 in Northwest Puerto Rico. Mutations in HPS genes affect the biogenesis of lysosome‐related organelles. The products of the HPS type 1 and 4 genes (i.e., HPS1 and HPS4) assemble to form a complex known as Biogenesis of Lysosome‐related Organelle Complex 3 (BLOC‐3). Here, we report the identification of two interacting regions in each HPS protein required to form the BLOC‐3. We found that HPS1 interacts with HPS4 in two regions, spanning amino acids 1–197 and 506–700 but not with the middle portion of HPS1 (250–505). In addition, HPS4 displays dual binding sites to HPS1, comprised by its N‐terminus (1–230) and a distinct region between residues 340–399. In vitro assays with truncated HPS1, mimicking mutations found in HPS1 patients, showed retention of some interaction with HPS4, suggesting the possibility to generate (a truncated form of) BLOC‐3 in these patients that could retain partial function and could possibly explain the variable progression of the pulmonary fibrosis in BLOC‐3 deficient patients.