Cytoplasmic dynein is a highly processive biomolecular motor protein with two motor domains (‘heads’) that generates force and motion toward the minus ends of microtubules in eukaryotic cells. It contains four AAA+ (AAA: ATPase associated with various cellular activities) domains per head that can bind ATP, and has the ability to take hundreds of nanometer-scale steps along microtubules before it dissociates and diffuses away. Such continuous movement requires coordination of the mechanochemical cycles of both motor domains so that the front head remains bound to the track while the rear head detaches and moves forward. However, the molecular mechanism that underlies dynein’s motion and force generation remains unknown. In this seminar, I will present our most recent combined structure-function and single-molecule optical tweezers studies that provide new insights into the coordination and force generation of the dynein motor domains. In addition, I will discuss the evolutionary differences in the force generation of metazoan and non-metazoan dyneins.
About the Gennerich Lab:
The research of our laboratory is focused on the development of advanced high-resolution and single-molecule microscopy techniques and their application to study how biomolecular motors work and generate biological motion. In particular, the Gennerich Lab combines single-molecule biophysics with cell biology and biochemistry to study the molecular mechanisms underlying cell division, intracellular organelle and mRNA transport, as well as the molecular mechanism of protein degradation. Current research is focused on the molecular function of the microtubule motor cytoplasmic dynein (a molecular machine that harnesses the chemical energy of ATP hydrolysis to perform mechanical work in eukaryotic cells) and its role in sister-chromatid separation and chromosome segregation, and the transport of mitochondria and mRNA. We use a multidisciplinary approach integrating ultrasensitive single-molecule assays (high-resolution optical trapping and single-molecule fluorescence microscopy), subwavelength resolution live cell imaging and genetic approaches such as homologous recombination and RNA interference to dissect the mechanisms of microtubule-based motor proteins and their associated biological processes. Our long-term goal is to understand the fundamental design principles of biomolecular motors and the molecular basis of human diseases with underlying defects in motor function.