The Mon1-Ccz1 Complex Is the GEF of the Late Endosomal Rab7 Homolog Ypt7
The Mon1-Ccz1 Complex Is the GEF of the Late Endosomal Rab7 Homolog Ypt7
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DOI：
10.1016/j.cub.2010.08.002
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发表时间：
2010-09-28
期刊：
影响因子：
9.2
通讯作者：
Ungermann, Christian
中科院分区：
文献类型：
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作者：
Nordmann, Mirjana;Cabrera, Margarita;Ungermann, Christian
Rab GTP酶协调膜融合反应[1]。Rab-GDP需要鸟嘌呤核苷酸交换因子（GEF）将其转化为活性GTP形式。然后，它与效应物如多聚体拴系复合物结合并支持融合[2]。GTP酶激活蛋白（GAP）促进GTP水解，使Rab活化。因此，GEF是聚变反应的关键活化剂[3，4]。Rab GEF家族是多样的，从多聚体复合物[5]到单体GEF [6-9]。在晚期内体，Rab 7激活对于内体成熟是至关重要的。酵母Rab 7同源物Ypt 7与同型融合和蛋白分选（HOPS）复合物结合[10，11]。其亚基Vps 39/Vam 6已被提议作为Ypt 7的GEF [12]和Rag GTdR Gtr 1 [13]，但其他遗传证据表明内体蛋白Ccz 1作为Ypt 7的GEF [14]。Ccz 1及其结合伴侣Mon 1与内体转运和成熟有关[15-20]。我们现在提供的证据表明，二聚的Mon 1-Ccz 1复合物是Rab 7/Ypt 7 GEF。Mon 1-Ccz 1复合物，但不是单独的蛋白质，抵消GAP功能在体内，拯救在体外融合的空泡携带Ypt 7-GDP，并促进核苷酸交换Ypt 7独立的Vps 39/HOPS。我们的数据表明，Mon 1-Ccz 1复合物通过激活晚期内体上的Ypt 7触发内体成熟。
Rab GTPases coordinate membrane fusion reactions [1]. Rab-GDP requires a guanine nucleotide exchange factor (GEF) for its conversion to the active GTP form. It then binds to effectors such as multimeric tethering complexes and supports fusion [2]. GTPase-activating proteins (GAPs) promote GTP hydrolysis to inactivate the Rab. GEFs are thus critical activators of fusion reactions [3, 4]. The Rab GEF family is diverse, ranging from multimeric complexes [5] to monomeric GEFs [6-9]. At the late endosome, Rab7 activation is critical for endosomal maturation. The yeast Rab7 homolog Ypt7 binds to the homotypic fusion and protein sorting (HOPS) complex [10, 11]. Its subunit Vps39/Vam6 has been proposed as a GEF for Ypt7 [12] and the Rag GTPase Gtr1 [13], but other genetic evidence has implicated the endosomal protein Ccz1 as a GEF for Ypt7 [14]. Ccz1 and its binding partner Mon1 have been linked to endosomal transport and maturation [15-20]. We now provide evidence that the dimeric Mon1-Ccz1 complex is the Rab7/Ypt7 GEF. The Mon1-Ccz1 complex, but neither protein alone, counteracts GAP function in vivo, rescues in vitro fusion of vacuoles carrying Ypt7-GDP, and promotes nucleotide exchange on Ypt7 independently of Vps39/HOPS. Our data indicate that the Mon1-Ccz1 complex triggers endosomal maturation by activating Ypt7 on late endosomes.