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

Neuron. 2004 Dec 2;44(5):809-21. doi: 10.1016/j.neuron.2004.11.019.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

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


  • Carrier Proteins
  • Microtubule-Associated Proteins
  • Ndel1 protein, mouse
  • Platelet Activating Factor
  • 1-Alkyl-2-acetylglycerophosphocholine Esterase
  • PAFAH1B1 protein, human
  • Pafah1b1 protein, mouse
  • Dyneins

Associated data

  • PDB/1VYH