LIS1 and NDEL1 coordinate the plus-end-directed transport of cytoplasmic dynein

EMBO J. 2008 Oct 8;27(19):2471-83. doi: 10.1038/emboj.2008.182. Epub 2008 Sep 11.

Abstract

LIS1 was first identified as a gene mutated in human classical lissencephaly sequence. LIS1 is required for dynein activity, but the underlying mechanism is poorly understood. Here, we demonstrate that LIS1 suppresses the motility of cytoplasmic dynein on microtubules (MTs), whereas NDEL1 releases the blocking effect of LIS1 on cytoplasmic dynein. We demonstrate that LIS1, cytoplasmic dynein and MT fragments co-migrate anterogradely. When LIS1 function was suppressed by a blocking antibody, anterograde movement of cytoplasmic dynein was severely impaired. Immunoprecipitation assay indicated that cytoplasmic dynein forms a complex with LIS1, tubulins and kinesin-1. In contrast, immunoabsorption of LIS1 resulted in disappearance of co-precipitated tubulins and kinesin. Thus, we propose a novel model of the regulation of cytoplasmic dynein by LIS1, in which LIS1 mediates anterograde transport of cytoplasmic dynein to the plus end of cytoskeletal MTs as a dynein-LIS1 complex on transportable MTs, which is a possibility supported by our data.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Alkyl-2-acetylglycerophosphocholine Esterase / genetics
  • 1-Alkyl-2-acetylglycerophosphocholine Esterase / metabolism*
  • Animals
  • Biological Transport / physiology
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Line
  • Cytoplasm / metabolism*
  • Dyneins / genetics
  • Dyneins / metabolism*
  • Fluorescence Recovery After Photobleaching
  • Humans
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism*
  • Microtubules / metabolism
  • Neurons / cytology
  • Neurons / physiology
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Swine
  • Tubulin / genetics
  • Tubulin / metabolism

Substances

  • Carrier Proteins
  • Microtubule-Associated Proteins
  • NDEL1 protein, human
  • Recombinant Fusion Proteins
  • TUBB3 protein, human
  • Tubulin
  • kinesin light-chain proteins
  • 1-Alkyl-2-acetylglycerophosphocholine Esterase
  • PAFAH1B1 protein, human
  • Dyneins