On and off controls within dynein-dynactin on native cargoes

Area of Science:

• Cellular biology
• Molecular motors
• Cytoskeletal dynamics

Background:

• The dynein-dynactin complex is a critical cellular nanomachine responsible for intracellular transport along microtubules.
• The precise roles of dynactin's separate interactions with dynein and microtubules remain incompletely understood.
• Understanding these interactions is vital for comprehending motor protein function and dysfunction.

Purpose of the Study:

• To investigate the functional significance of the dynactin-dynein and dynactin-microtubule interactions.
• To determine how perturbing these interactions affects dynein-dynactin motor activity under load.

Main Methods:

• Targeted disruption of dynein-dynactin interactions on phagosomes isolated from cells.
• Utilizing optical trapping to analyze the behavior of single dynein-dynactin complexes.
• Quantifying motor on-rates and off-rates under force-generating conditions.

Main Results:

• Disrupting the dynactin-dynein interaction decreased the motor's rate of binding to microtubules.
• Perturbing the dynactin-microtubule interaction significantly increased the motor's detachment rate when under load.
• The dynactin-microtubule linkage is essential for maintaining motor persistence against applied force.

Conclusions:

• The dynactin-microtubule interaction is critical for dynein-dynactin motor persistence under load.
• This finding provides insight into how disease-related mutations affecting dynein-dynactin cause cellular dysfunction.
• Detachment against load is an underappreciated aspect of dynein-dynactin function relevant to disease mechanisms.