The P3018S disease variant reveals how dynein's trailing motor sets ensemble velocity

Area of Science:

• Molecular motor function
• Neurodevelopmental biology
• Cellular transport mechanisms

Background:

• Mutations in DYNC1H1 cause neurodevelopmental disorders.
• The precise impact of specific variants on dynein function is not well understood.
• Cytoplasmic dynein is crucial for intracellular transport.

Purpose of the Study:

• To characterize the disease-associated P3018S mutation in DYNC1H1.
• To investigate how this mutation affects dynein motor function and complex assembly.
• To elucidate mechanisms of motor-motor stimulation in multi-dynein systems.

Main Methods:

• Biochemical characterization of P3018S dynein within Dynein-dynactin-BicD2 (DDB) complexes.
• In vitro motility assays to measure velocity and stall force.
• Analysis of mixed wild-type and mutant dynein assemblies.

Main Results:

• P3018S dynein exhibits reduced velocity and stall force but retains Lis1 interaction and responsiveness.
• The trailing dynein motor dictates ensemble velocity in mixed assemblies.
• Leading dynein motors enhance trailing motor velocity by approximately 130% via Lis1 Interaction domain (LIC) interaction.

Conclusions:

• The P3018S mutation impairs dynein motor function, contributing to neurodevelopmental disorders.
• A novel mechanism of leading-to-trailing motor stimulation exists within multi-dynein assemblies.
• Evolutionary conservation in some species suggests functional relevance of the serine residue at this position.