How does a registry change in dynein's coiled-coil stalk drive binding of dynein to microtubules?

Area of Science:

• Molecular Biology
• Biophysics
• Structural Biology

Background:

• Dynein is a crucial motor protein for intracellular transport, utilizing ATP to move along microtubules.
• The microtubule-binding domain (MTBD) is connected to the ATP-binding core via a coiled-coil stalk.
• Previous models suggested a registry shift in the stalk modulates dynein's microtubule binding affinity, but the high-affinity structure remained elusive.

Purpose of the Study:

• To elucidate the structural mechanism of the high-affinity dynein-microtubule binding state.
• To model the all-atom structure of the high-affinity MTBD bound to microtubules.
• To understand the role of specific residues and structural dynamics in modulating dynein-microtubule affinity.

Main Methods:

• Anisotropic network model simulations
• Protein-protein docking
• All-atom molecular dynamics simulations

Main Results:

• An all-atom model of the high-affinity MTBD-microtubule complex was generated.
• Coiled-coil helix sliding was significantly reduced near proline residues at the stalk-MTBD boundary.
• Cyclic movements of MTBD helices formed a new salt bridge at the binding interface, explaining the high-affinity interaction.

Conclusions:

• The study proposes a novel mechanism for high-affinity dynein-microtubule binding involving reduced helix sliding and salt bridge formation.
• Conserved residues, including prolines and nonpolar residues, play critical roles in regulating the stalk-MTBD interaction and binding affinity.
• The findings provide insights into the dynamic regulation of motor protein function at the molecular level.