Regulation of cytoplasmic dynein ATPase by Lis1

Mariano T. Mesngon, Cataldo Tarricone, Sachin Hebbar, Aimee M. Guillotte, E. William Schmitt, Lorene Lanier, Andrea Musacchio, Stephen J. King, Deanna S. Smith

Research output: Contribution to journalArticlepeer-review

68 Scopus citations

Abstract

Mutations in Lis1 cause classical lissencephaly, a developmental brain abnormality characterized by defects in neuronal positioning. Over the last decade, a clear link has been forged between Lis1 and the microtubule motor cytoplasmic dynein. Substantial evidence indicates that Lis1 functions in a highly conserved pathway with dynein to regulate neuronal migration and other motile events. Yeast two-hybrid studies predict that Lis1 binds directly to dynein heavy chains (Sasaki et al., 2000; Tai et al., 2002), but the mechanistic significance of this interaction is not well understood. We now report that recombinant Lis1 binds to native brain dynein and significantly increases the microtubule-stimulated enzymatic activity of dynein in vitro. Lis1 does this without increasing the proportion of dynein that binds to microtubules, indicating that Lis1 influences enzymatic activity rather than microtubule association. Dynein stimulation in vitro is not a generic feature of microtubule-associated proteins, because tau did not stimulate dynein. To our knowledge, this is the first indication that Lis1 or any other factor directly modulates the enzymatic activity of cytoplasmic dynein. Lis1 must be able to homodimerize to stimulate dynein, because a C-terminal fragment (containing the dynein interaction site but missing the self-association domain) was unable to stimulate dynein. Binding and colocalization studies indicate that Lis1 does not interact with all dynein complexes found in the brain. We propose a model in which Lis1 stimulates the activity of a subset of motors, which could be particularly important during neuronal migration and long-distance axonal transport.

Original languageEnglish (US)
Pages (from-to)2132-2139
Number of pages8
JournalJournal of Neuroscience
Volume26
Issue number7
DOIs
StatePublished - Feb 15 2006

Keywords

  • Axon transport
  • Dynein
  • Lis1
  • Lissencephaly
  • Microtubules
  • Neuronal migration

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