Structural insights into functional overlapping and differentiation among myosin V motors

Area of Science:

• Molecular Biology
• Structural Biology
• Cell Biology

Background:

• Myosin V (MyoV) motors are essential for intracellular transport of various cargoes like vesicles, organelles, and proteins.
• Understanding the structural basis of MyoV function is crucial for deciphering cellular transport mechanisms.

Purpose of the Study:

• To determine the structures of the cargo-binding domains (CBDs) for all three human Myosin V paralogs (MyoVa, MyoVb, MyoVc).
• To elucidate the structural basis for functional differentiation among MyoV paralogs.
• To investigate the regulatory mechanisms, including dimerization and autoinhibition, of MyoV motors.

Main Methods:

• X-ray crystallography was used to solve the structures of the cargo-binding domains (CBDs) of human Myosin Va, Vb, and Vc.
• Structural analysis was performed to identify conserved and divergent features, cargo-binding sites, and motor-binding sites.

Main Results:

• Structures revealed subtle differences driving functional specialization among human MyoV paralogs.
• A novel redox mechanism controlling CBD dimerization was identified, unique to the MyoVc subclass.
• Cargo- and motor-binding sites were structurally mapped, showing conserved residues for peroxisome adaptor recognition and high-resolution insights into CBD-mediated autoinhibition.

Conclusions:

• The structural insights provide a foundation for understanding the functional diversity and regulation of Myosin V motors.
• The findings highlight the importance of the cargo-binding domain in MyoV motor activity, autoinhibition, and cargo specificity.
• This study advances our knowledge of the molecular mechanisms governing intracellular transport mediated by Myosin V motors.