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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 alpha 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 alpha2/alpha2 PAF-AH homodimer. One LIS1 homodimer binds symmetrically to one alpha2/alpha2 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 alpha2/alpha2 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.

Original publication

DOI

10.1016/j.neuron.2004.11.019

Type

Journal article

Journal

Neuron

Publication Date

02/12/2004

Volume

44

Pages

809 - 821

Keywords

1-Alkyl-2-acetylglycerophosphocholine Esterase, Amino Acid Sequence, Animals, Binding, Competitive, Carrier Proteins, Cell Line, Dyneins, Humans, Mice, Microtubule-Associated Proteins, Molecular Conformation, Molecular Sequence Data, Platelet Activating Factor, Protein Structure, Tertiary, Signal Transduction, Spodoptera