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Allosteric conformational change cascade in cytoplasmic dynein revealed by structure-based molecular simulations

Shintaroh Kubo1, Wenfei Li2, Shoji Takada1

  • 1Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto, Japan.

Plos Computational Biology
|September 12, 2017
PubMed

Insights

Cytoplasmic dynein uses ATP hydrolysis in its AAA+ ring to move along microtubules. Molecular simulations reveal how conformational changes in the ring drive dynein

Area of Science:

  • Molecular Biology
  • Biophysics
  • Cellular Motor Proteins

Background:

  • Cytoplasmic dynein is a large molecular motor essential for intracellular transport, moving towards the minus end of microtubules.
  • Dynein's structure features a six-module AAA+ ring for ATP hydrolysis, positioned distally from its microtubule-binding domain (MTBD).
  • The mechanism of allosteric communication between the AAA+ ring and MTBD, crucial for dynein's motility, remains poorly understood.

Purpose of the Study:

  • To investigate the allosteric conformational changes in the dynein motor domain during its power and recovery stroke cycles.
  • To elucidate the molecular mechanisms underlying the communication between the AAA+ ring and the MTBD.

Main Methods:

  • Comprehensive molecular simulations of the dynein motor domain.
  • Utilized pre- and post-power-stroke structural data as simulation starting points.
  • Analyzed nucleotide-dependent transitions within the AAA+ ring and their propagation.

Main Results:

  • During the power stroke, N-terminal linker movement initiated a cascade from AAA1, propagating circularly around the AAA+ ring to AAA6.
  • The recovery stroke began with AAA6/C-terminal transition, triggering a bifurcated cascade clockwise and anti-clockwise around the ring.
  • Conformational changes in the MTBD were consistently regulated by the AAA4 and AAA5/Strut modules in both stroke cycles.

Conclusions:

  • The study reveals distinct, yet coordinated, allosteric pathways within the dynein AAA+ ring during power and recovery strokes.
  • Identified key regulatory roles of specific AAA+ modules (AAA4, AAA5/Strut) in coupling ATP hydrolysis to MTBD function.
  • Provides a mechanistic basis for understanding how dynein achieves directional movement along microtubules.

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