The structure of the N-terminal domain of the product of the lissencephaly gene Lis1 and its functional implications
The structure of the N-terminal domain of the product of the lissencephaly gene Lis1 and its functional implications
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DOI：
10.1016/j.str.2004.03.024
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发表时间：
2004-06-01
期刊：
影响因子：
5.7
通讯作者：
Derewenda, ZS
中科院分区：
文献类型：
--
作者：
Kim, MH;Cooper, DR;Derewenda, ZS
Lis1基因的突变会导致无脑(平滑大脑)，这是一种由于有丝分裂后神经元迁移到大脑皮层正确目的地的能力受损而导致的衰弱发育综合征。序列相似性表明，Lis1蛋白含有一个C-末端的七叶片β-螺旋桨结构域，而N-末端片段的结构包括LISH(Lis-Homology)基序，这是一种在100多种真核蛋白质中发现的模式，功能未知。我们给出了小鼠LIS1 N-末端结构域的1.75埃分辨率晶体结构，并证明了LISH基序是一个新的、热力学上非常稳定的二聚化结构域。这种结构解释了一种低度无脑畸形的分子基础。
Mutations in the Lis1 gene result in lissencephaly (smooth brain), a debilitating developmental syndrome caused by the impaired ability of postmitotic neurons to migrate to their correct destination in the cerebral cortex. Sequence similarities suggest that the LIS1 protein contains a C-terminal seven-blade beta-propeller domain, while the structure of the N-terminal fragment includes the LisH (Lis-homology) motif, a pattern found in over 100 eukaryotic proteins with a hitherto unknown function. We present the 1.75 Angstrom resolution crystal structure of the N-terminal domain of mouse LIS1, and we show that the LisH motif is a novel, thermodynamically very stable dimerization domain. The structure explains the molecular basis of a low severity form of lissencephaly.