Novel functional features of the Lis-H domain - Role in protein dimerization, half-life and cellular localization
Novel functional features of the Lis-H domain - Role in protein dimerization, half-life and cellular localization
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DOI：
10.4161/cc.4.11.2151
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发表时间：
2005-11-01
期刊：
影响因子：
4.3
通讯作者：
Reiner, O
中科院分区：
文献类型：
--
作者：
Gerlitz, G;Darhin, E;Reiner, O
保守蛋白质基序的存在通常意味着共同的功能特征。在这里，我们专注于LisH（LIS 1同源性）结构域，它存在于多种蛋白质中，并专注于三种与人类遗传疾病有关的结构域：LIS 1，Transducin beta-like 1X（TBL 1）和Oral-facial-digital type 1（OFD 1）。最近解决的结构的LisH域的N-末端区域的LIS 1描绘它作为一个新的二聚化基序。我们的研究结果表明，LIS 1和TBL 1的LisH结构域是体外寡聚化所必需的。此外，我们的研究揭示了新的LisH基序在体内的功能。保守的LisH氨基酸突变显着降低了LIS 1，TBL 1和OFD 1的蛋白质半衰期，并显着影响这些蛋白质的特定细胞内定位。在LisH结构域中突变的LIS 1诱导其定位于肌动蛋白丝。在LisH结构域中突变的TBL 1没有被输入到细胞核中。OFD 1的突变改变了其在高尔基体的定位，在某些情况下也改变了其在细胞核的定位。总之，LisH结构域可能参与蛋白质二聚化，影响蛋白质半衰期，并可能影响特定的细胞定位。我们的研究结果可以预测，LisH基序内的突变可能会导致与遗传疾病相关的基因的致病后果。
The presence of a conserved protein motif usually implies common functional features. Here, we focused on the LisH (LIS1 homology) domain, which is found in multiple proteins, and have focused on three involved in human genetic diseases; LIS1, Transducin beta-like 1X (TBL1) and Oral-facial-digital type 1 (OFD1). The recently solved structure of the LisH domain in the N-terminal region of LIS1 depicted it as a novel dimerization motif. Our findings indicated that the LisH domain of both LIS1 and TBL1 is essential for in vitro oligomerization. Furthermore, our study disclosed novel in vivo features of the LisH motif. Mutations in conserved LisH amino acids significantly reduced both the protein half-life of LIS1, TBL1, and OFD1, and dramatically affected specific intracellular localizations of these proteins. LIS1 mutated in the LisH domain induced its localization to the actin filaments. TBL1 mutated in the LisH domain was not imported into the nucleus. Mutations in OFD1 modified its localization to the Golgi apparatus and in some cases also to the nucleus. In summary, the LisH domain may participate in protein dimerization, affect protein half-life, and may influence specific cellular localizations. Our results allow the prediction that mutations within the LisH motif are likely to result in pathogenic consequences in genes associated with genetic diseases.