Molecular mechanism of dynein-dynactin complex assembly by LIS1

Science. 2024 Mar 29;383(6690):eadk8544. doi: 10.1126/science.adk8544. Epub 2024 Mar 29.


Cytoplasmic dynein is a microtubule motor vital for cellular organization and division. It functions as a ~4-megadalton complex containing its cofactor dynactin and a cargo-specific coiled-coil adaptor. However, how dynein and dynactin recognize diverse adaptors, how they interact with each other during complex formation, and the role of critical regulators such as lissencephaly-1 (LIS1) protein (LIS1) remain unclear. In this study, we determined the cryo-electron microscopy structure of dynein-dynactin on microtubules with LIS1 and the lysosomal adaptor JIP3. This structure reveals the molecular basis of interactions occurring during dynein activation. We show how JIP3 activates dynein despite its atypical architecture. Unexpectedly, LIS1 binds dynactin's p150 subunit, tethering it along the length of dynein. Our data suggest that LIS1 and p150 constrain dynein-dynactin to ensure efficient complex formation.

MeSH terms

  • 1-Alkyl-2-acetylglycerophosphocholine Esterase*
  • Adaptor Proteins, Signal Transducing* / chemistry
  • Adaptor Proteins, Signal Transducing* / metabolism
  • Cryoelectron Microscopy
  • Dynactin Complex* / chemistry
  • Dynactin Complex* / genetics
  • Dynactin Complex* / metabolism
  • Dyneins* / chemistry
  • Dyneins* / genetics
  • Dyneins* / metabolism
  • HeLa Cells
  • Humans
  • Microtubule-Associated Proteins* / chemistry
  • Microtubule-Associated Proteins* / metabolism
  • Microtubules / metabolism
  • Nerve Tissue Proteins* / chemistry
  • Nerve Tissue Proteins* / metabolism
  • Protein Binding
  • Protein Interaction Mapping
  • WD40 Repeats


  • Dynactin Complex
  • Dyneins
  • Microtubule-Associated Proteins
  • PAFAH1B1 protein, human
  • 1-Alkyl-2-acetylglycerophosphocholine Esterase
  • MAPK8IP3 protein, human
  • Nerve Tissue Proteins
  • Adaptor Proteins, Signal Transducing