Coupling PAF signaling to dynein regulation: Structure of LIS1 in complex with PAF-Acetylhydrolase
Coupling PAF signaling to dynein regulation: Structure of LIS1 in complex with PAF-Acetylhydrolase
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DOI：
10.1016/s0896-6273(04)00751-2
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发表时间：
2004-12-02
期刊：
影响因子：
16.2
通讯作者：
Musacchio, A
中科院分区：
文献类型：
--
作者：
Tarricone, C;Perrina, F;Musacchio, A
LIS1基因的突变导致无脑畸形，这是一种人类神经元迁移障碍。LIS1结合动力蛋白和动力蛋白相关蛋白Nde1（以前称为NudE）、Ndel1（以前称为NUDEL）和CLIP-170，以及脑细胞质血小板活化因子乙酰水解酶（PAF-AH）的催化二聚体。这两种不同调控途径的耦合机制尚不清楚。我们报道了LIS1与(α (2)/ α (2) PAF-AH同二聚体的复合物结构。一个LIS1同型二聚体通过LIS1 β螺旋桨高度保守的顶面与一个α (2)/ α(2)同型二聚体对称结合。LIS1的同一表面包含导致无脑畸形的突变位点，并与假定的动力蛋白结合表面重叠。Ndel1与LIS1的α (2)/ α(2)同二聚体竞争，但相互作用很复杂，需要LIS1的N端和c端结构域。我们的数据表明，当LIS1分子从与乙酰水解酶的络合物切换到与Ndel1的络合物时，经历了主要的构象重排。
Mutations in the LIS1 gene cause lissencephaly, a human neuronal migration disorder. LIS1 binds dynein and the dynein-associated proteins Nde1 (formerly known as NudE), Ndel1 (formerly known as NUDEL), and CLIP-170, as well as the catalytic a dimers of brain cytosolic platelet activating factor acetylhydrolase (PAF-AH). The mechanism coupling the two diverse regulatory pathways remains unknown. We report the structure of LIS1 in complex with the (alpha(2)/alpha(2) PAF-AH homodimer. One LIS1 homodimer binds symmetrically to one alpha(2)/alpha(2) homodimer via the highly conserved top faces of the LIS1 beta propellers. The same surface of LIS1 contains sites of mutations causing lissencephaly and overlaps with a putative dynein binding surface. Ndel1 competes with the alpha(2)/alpha(2) homodimer for LIS1, but the interaction is complex and requires both the N- and C-terminal domains of LIS1. Our data suggest that the LIS1 molecule undergoes major conformational rearrangement when switching from a complex with the acetylhydrolase to the one with Ndel1.