A divalent interaction between HPS1 and HPS4 is required for the formation of the biogenesis of lysosome-related organelle complex-3 (BLOC-3)

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• 作者：Carmelo Carmona-Rivera^a ; ^b ; ¹ ; Dimitre R. Simeonov^b ; Nicholas D. Cardillo^b ; William A. Gahl^b ; Carmen L. Cadilla^a ; ^{carmen.cadilla@upr.edu}
• 关键词：BLOC ; biogenesis of lysosome-related organelles ; DUF ; domain of unknown function ; DMEM ; Dulbecco's modified Eagle's medium ; EGFP ; enhanced green fluorescent protein ; FBS ; fetal bovine serum ; HA ; hemagglutinin ; HPS ; Hermansky&ndash ; Pudlak syndrome ; IgG ; im
• 刊名：Biochimica et Biophysica Acta (BBA)/Molecular Cell Research
• 出版年：2013
• 出版时间：March, 2013
• 年：2013
• 卷：1833
• 期：3
• 页码：468-478
• 全文大小：1349 K

文摘

Hermansky-Pudlak syndrome (HPS) is a group of rare autosomal recessive disorders characterized by oculocutaneous albinism, a bleeding tendency, and sporadic pulmonary fibrosis, granulomatous colitis or infections. Nine HPS-causing genes have been identified in humans. HPS-1 is the most severe subtype with a prevalence of ~ 1/1800 in northwest Puerto Rico due to a founder mutation in the HPS1 gene. Mutations in HPS genes affect the biogenesis of lysosome-related organelles such as melanosomes in melanocytes and platelet dense granules. Two of these genes (HPS1 and HPS4) encode the HPS1 and HPS4 proteins, which assemble to form a complex known as Biogenesis of Lysosome-related Organelle Complex 3 (BLOC-3). We report the identification of the interacting regions in HPS1 and HPS4 required for the formation of this complex. Two regions in HPS1, spanning amino acids 1-249 and 506-700 are required for binding to HPS4; the middle portion of HPS1 (residues 250-505) is not required for this interaction. Further interaction studies showed that the N-termini of HPS1 and HPS4 interact with each other and that a discrete region of HPS4 (residues 340-528) interacts with both the N- and C-termini of the HPS1 protein. Several missense mutations found in HPS-1 patients did not affect interaction with HPS4, but some mutations involving regions interacting with HPS4 caused instability of HPS1. These observations extend our understanding of BLOC-3 assembly and represent an important first step in the identification of domains responsible for the biogenesis of lysosome-related organelles.