Coupling PAF signaling to dynein regulation: Structure of LIS1 in complex with PAF-acetylhydrolase

Cataldo Tarricone, Franco Perrina, Silvia Monzani, Lucia Massimiliano, Myung Hee Kim, Zygmunt S. Derewenda, Stefan Knapp, Li Huei Tsai, Andrea Musacchio

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Abstract

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 α 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 α 22 PAF-AH homodimer. One LIS1 homodimer binds symmetrically to one α 22 homodimer via the highly conserved top faces of the LIS1 β propellers. The same surface of LIS1 contains sites of mutations causing lissencephaly and overlaps with a putative dynein binding surface. Ndel1 competes with the α 2/ α 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.

Original languageEnglish
Pages (from-to)809-821
Number of pages13
JournalNeuron
Volume44
Issue number5
DOIs
Publication statusPublished - Dec 2 2004

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ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Tarricone, C., Perrina, F., Monzani, S., Massimiliano, L., Kim, M. H., Derewenda, Z. S., Knapp, S., Tsai, L. H., & Musacchio, A. (2004). Coupling PAF signaling to dynein regulation: Structure of LIS1 in complex with PAF-acetylhydrolase. Neuron, 44(5), 809-821. https://doi.org/10.1016/j.neuron.2004.11.019