Structural basis of cargo recognitions for class V myosins

Area of Science:

• Molecular Biology
• Structural Biology
• Cell Biology

Background:

• Class V myosins (MyoV) are essential motor proteins that transport various cellular cargos.
• The globular tail domain (GTD) of MyoV mediates cargo recognition, but the specificity mechanisms remain largely unknown.
• Understanding MyoV-GTD interactions is critical for elucidating cellular transport processes and associated human diseases.

Purpose of the Study:

• To determine the structural basis of cargo recognition by the Class V myosin A globular tail domain (MyoVa-GTD).
• To investigate how mutations associated with human diseases affect MyoV-GTD structure and function.
• To compare cargo-binding mechanisms across different MyoV isoforms and species.

Main Methods:

• X-ray crystallography was used to solve the structures of MyoVa-GTD in apo-form and complexed with melanophilin and Rab interacting lysosomal protein-like 2.
• Biochemical analyses were performed to assess cargo-binding specificities.
• Comparative structural analysis was conducted for different MyoV isoforms and species.

Main Results:

• The apo-MyoVa-GTD structure revealed that disease-associated mutations likely disrupt GTD folding.
• The MyoVa-GTD/cargo complex structures identified two distinct cargo-binding surfaces utilizing charge-charge and hydrophobic interactions.
• Structural and biochemical data highlighted isoform-specific and species-specific differences in MyoV cargo recognition.

Conclusions:

• The determined MyoVa-GTD structures provide a detailed molecular framework for understanding vertebrate Class V myosin function.
• These findings offer insights into the molecular basis of diseases linked to MyoV dysfunction.
• The study reveals conserved and divergent mechanisms of cargo binding in Class V myosins across eukaryotes.