Allosteric communication in myosin V: from small conformational changes to large directed movements

Area of Science:

• Molecular Biology
• Biophysics
• Structural Biology

Background:

• The rigor to post-rigor transition in myosin is critical for the Lymn-Taylor functional cycle.
• This transition, induced by ATP binding, causes actomyosin complex dissociation post-powerstroke.

Purpose of the Study:

• To develop a normal mode superposition model for the myosin rigor to post-rigor transition.
• To elucidate the mechanism of actomyosin dissociation and ATP/actin binding mutual exclusion.

Main Methods:

• Utilized X-ray structures of myosin V.
• Developed a normal mode superposition model to simulate the transition path.
• Analyzed rigid-body motions of subdomains and interface residues.

Main Results:

• Identified rigid-body subdomain motions and specific residue movements as key transition elements.
• Demonstrated allosteric communication between the nucleotide binding site and U50/L50 cleft via ATP-induced local changes.
• Revealed that ATP binding stabilizes switch I and P-loop interactions, initiating U50/L50 cleft opening and weakening myosin-actin binding.

Conclusions:

• The model elucidates subdomain coupling, explaining the mutual exclusion of ATP and actin binding.
• The mechanism of converter-motor head uncoupling during the transition is explained.
• The origin of the central beta-sheet untwisting in the rigor to post-rigor transition is described.