Reduced pigmentation (rp), a mouse model of Hermansky-Pudlak syndrome, encodes a novel component of the BLOG-1 complex
Reduced pigmentation (rp), a mouse model of Hermansky-Pudlak syndrome, encodes a novel component of the BLOG-1 complex
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DOI：
10.1182/blood-2004-04-1538
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发表时间：
2004-11-15
期刊：
影响因子：
20.3
通讯作者：
Peters, LL
中科院分区：
文献类型：
--
作者：
Gwynn, B;Martina, JA;Peters, LL
Hermansky-Pudlak综合征(HPS)是一种细胞器生物发生障碍，影响溶酶体、黑素体和血小板致密小体。7个基因导致人类HPS(HPS1-HPS7)，至少15个非等位基因突变导致小鼠HPS。在已知其功能的情况下，HPS蛋白参与细胞器生物发生过程中的蛋白质运输和囊泡对接/融合事件。HPS相关基因参与至少4种不同的蛋白质复合体：接合复合体AP-3；溶酶体相关或盖尔复合体的生物发生1(BLOC-1)，由4种HPS蛋白(Pallidin、muted、cappuccino、HPS7/Sandy)组成；BLOC-2，由HPS6/红宝石眼、HPS5/红宝石眼-2和HPS3/可可组成；以及BLOC-3，由HPS1/苍耳和HPS4/轻耳组成。在这里，我们报告了小鼠HPS突变减少色素沉着(RP)的克隆。我们发现野生型RP基因编码一种新的、广泛表达的195个氨基酸的蛋白质，它与人类同源基因有87%的氨基酸同源性，并定位于细胞质结构。此外，我们还证明了磷酸化的RP是BLOC-1复合体的一部分。在突变的RP/RP小鼠中，提前终止密码子在79个氨基酸后截断蛋白质。包括PIP在内的所有5个已知BLOC-1组分的缺陷都会导致小鼠严重的HPS，这表明BLOC-1的亚基是非冗余的，并且BLOC-1在细胞器的生物发生中发挥着关键作用。(C)2004年，由美国血液病学会提供。
Hermansky-Pudlak syndrome (HPS), a disorder of organelle biogenesis, affects lysosomes, melanosomes, and platelet dense bodies. Seven genes cause HPS in humans (HPS1-HPS7) and at least 15 nonallelic mutations cause HPS in mice. Where their function is known, the HPS proteins participate in protein trafficking and vesicle docking/fusion events during organelle biogenesis. HPS-associated genes participate in at least 4 distinct protein complexes: the adaptor complex AP-3; biogenesis of lysosome-related or ganelles complex 1 (BLOC-1), consisting of 4 HPS proteins (pallidin, muted, cappuccino, HPS7/sandy); BLOC-2, consisting of HPS6/ruby-eye, HPS5/ruby-eye-2, and HPS3/cocoa; and BLOC-3, consisting of HPS1/pale ear and HPS4/light ear. Here, we report the cloning of the mouse HPS mutation reduced pigmentation (rp). We show that the wild-type rp gene encodes a novel, widely expressed 195-amino acid protein that shares 87% amino acid identity with its human orthologue and localizes to punctate cytoplasmic structures. Further, we show that phosphorylated RP is part of the BLOC-1 complex. In mutant rp/rp mice, a premature stop codon truncates the protein after 79 amino acids. Defects in all the 5 known components of BLOC-1, including PIP, cause severe HPS in mice, suggesting that the subunits are nonredundant and that BLOC-1 plays a key role in organelle biogenesis. (C) 2004 by The American Society of Hematology.