Characterization of the Rab7K157N mutant protein associated with Charcot-Marie-Tooth type 2B
Characterization of the Rab7K157N mutant protein associated with Charcot-Marie-Tooth type 2B
复制标题
DOI：
10.1016/j.bbrc.2008.05.060
复制
发表时间：
2008-07-25
影响因子：
3.1
通讯作者：
Bucci, Cecilia
中科院分区：
文献类型：
--
作者：
De Luca, Azzurra;Progida, Cinzia;Bucci, Cecilia
四个错义突变，靶向高度保守的氨基酸残基的小GTTRab 7，已与Charcot-Marie-Tooth（CMT）2B型表型。CMT 2B周围轴突神经病的特征是严重的感觉丧失，通常并发感染、关节病和截肢。在这里，我们研究了Rab 7 K157 N突变蛋白的生物化学和功能特性。有趣的是，与野生型蛋白质相比，Kab 7 K157 N显示出改变的核苷酸交换速率和GTP水解。在HeLa细胞中表达的蛋白质大部分与GTP结合。此外，Rab 7 K157 N能够恢复先前被Rab 7沉默抑制的EGF降解。总之，这些数据表明Rab 7 K157 N与引起CMT 2B的其他三种突变蛋白类似，主要以GTP结合形式存在，并表现为活性突变体。因此，Rab 7蛋白的活化形式导致CMT 2B疾病。(C)2008年爱思唯尔公司All rights reserved.
Four missense mutations, that target highly conserved amino acid residues in the small GTPase Rab7, have been associated with the Charcot-Marie-Tooth (CMT) type 2B phenotype. CMT2B peripheral axonal neuropathies are characterized by severe sensory loss, often complicated by infections, arthropathy, and amputations. Here, we have investigated the biochemical and functional properties of the Rab7 K157N mutated protein. Interestingly, Kab7 K157N showed altered nucleotide exchange rate and GTP hydrolysis compared to the wild type protein. Consistently, the majority of the expressed protein in HeLa cells was bound to GTP. In addition, Rab7 K157N was able to restore EGF degradation, previously inhibited by Rab7 silencing. Altogether these data indicate that Rab7 K157N, similarly to the other three mutated proteins causative of CMT2B, is predominantly in the GTP-bound form and behaves as an active mutant. Therefore, activated forms of Rab7 protein cause the CMT2B disease. (C) 2008 Elsevier Inc. All rights reserved.