Research at the Cooke Lab

Motor proteins perform roles in numerous biological processes, including: muscle contraction, cell division and the movement of intracellular organelles. We study the mechanism of action of two classes of motor proteins, the myosin family and the kinesin family, which share a structural homology. One long-range goal of our laboratory is to understand the molecular mechanisms by which these two classes of motor proteins generate force. 

The interaction of two proteins, actin and myosin, produces the force of muscle contraction and is also involved in the motility of all eukaryotic cells. We have used spectroscopic probes, both paramagnetic and fluorescent, to measure the orientation and conformation of both actin and myosin in active muscle fibers. 

Kinesin motors are smaller than myosin but generate forces and displacements that are similar. To monitor conformational changes in this motor we have placed paramagnetic probes on active elements. This work, carried out in collaboration with the laboratory of Dr. Ron Vale, led to the first molecular model of kinesin motility. 

Another goal of the lab is to determine how muscle fibers adapt to intense activity and fatigue. Using muscle fibers that are permeable, we can simulate the intracellular conditions that occur in fatigued muscle. These studies have shown that the accumulation of a number of metabolic products in the interior of the muscle cell can account for some of the fatigue felt by the long distance runner, but it does not explain all of it.  A subunit of myosin becomes phosphorylated during heavy use.  Our recent results suggest that myosin phosphorylation works synergistically with metabolite accumulation to inhibit fiber shortening velocity.   

The relevance of our research is to explain the complex behavior of muscles (skeletal, smooth and cardiac), as well as the motility of non muscle cells, in terms of the interactions of the motor proteins. Our results will help develop more rational methods to manipulate muscle contraction and cell motility for medical purposes.