The structure of the N-terminal domain of the product of the lissencephaly gene Lis1 and its functional implications

Structure. 2004 Jun;12(6):987-98. doi: 10.1016/j.str.2004.03.024.


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 A 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.

Publication types

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

MeSH terms

  • 1-Alkyl-2-acetylglycerophosphocholine Esterase
  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Dimerization
  • Dose-Response Relationship, Drug
  • Guanidine / pharmacology
  • Mice
  • Microtubule-Associated Proteins / chemistry*
  • Microtubule-Associated Proteins / metabolism
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation
  • Protein Conformation
  • Protein Denaturation
  • Protein Folding
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Sequence Homology, Amino Acid
  • Thermodynamics


  • Microtubule-Associated Proteins
  • 1-Alkyl-2-acetylglycerophosphocholine Esterase
  • Pafah1b1 protein, mouse
  • Guanidine

Associated data

  • PDB/1UUJ