Part II: Single Molecule Approaches for Understanding Dynein
|Download:||This Video Subtitled Videos: English|
|Resources:||Transcript(.txt)(.xls)Related Articles Teaching Tools|
|Trouble Viewing? Try it on iTunes.Report a problem.|
Molecular motor proteins are fascinating enzymes that power much of the movement performed by living organisms. In the first part of this lecture, I will provide an overview of the motors that move along cytoskeletal tracks (kinesin and dynein which move along microtubules and myosin which moves along actin). The main focus of this lecture is on how motor proteins work. How does a nanoscale protein convert energy from ATP hydrolysis into unidirectional motion and force production? What tools do we have at our disposal to study them? The first part of the lecture will focus on these questions for kinesin (a microtubule-based motor) and myosin (an actin-based motor), since they have been the subject of extensive studies and good models for their mechanisms have emerged. I conclude by discussing the importance of understanding motor proteins for human disease, in particular illustrating a recent biotechnology effort from Cytokinetics, Inc. to develop drugs that activate cardiac myosins to improve cardiac contractility in patients suffering from heart failure. The first part of the lecture is directed to a general audience or a beginning graduate class.
In the second part of this lecture, I will discuss our laboratory's current work on the mechanism of movement by dynein, a motor protein about which we still know very little. This is a research story in progress, where some advances have been made. However, much remains to be done in order to understand how this motor works.
The third (last) part of the lecture is on mitosis, the process by which chromosomes are aligned and then segregated during cell division. I will describe our efforts to find new proteins that are important for mitosis through a high throughput RNAi screen. I will discuss how we technically executed the screen and then focus on new proteins that are we discovered that are involved in generating the microtubules that compose the mitotic spindle. I also discuss the medical importance of studying mitosis, including the development of drugs targeted to mitotic motor proteins, which are currently undergoing testing in clinical trials.
Ron Vale is Professor and Chair of Cellular and Molecular Pharmacology at the University of California, San Francisco, where he has been on faculty since 1987. He also has been an investigator of the Howard Hughes Medical Institute since 1995.
Vale received a B.A. degree in biology and chemistry from the University of California, Santa Barbara (1980), and a Ph.D. degree in neuroscience from Stanford University (1985). His graduate and postdoctoral studies at the Marine Biological Laboratory led to the discovery of kinesin, a microtubule-based motor protein.
Dr. Vale’s honors include the Pfizer Award in enzyme chemistry, the Young Investigator Award from the Biophysical Society, and election to the National Academy of Sciences and the American Academy of Arts and Sciences. In 2012, Vale shared the Lasker Award for Basic Medical Research. Besides studying the mechanism of motor proteins (the subject of this lecture), Vale’s laboratory using RNAi and high resolution microscopy to study mitosis and cell shape, examines signal transduction by single molecule microscopy, and biochemistry/cell biology of microtubule plus end binding proteins.
- iBiology Hangout: Live Q&A with Ron Vale
- Margaret Gardel iBioMagazine: What is Cytoplasm
- Ron Vale iBioEducation Lecture: Molecular Motors
- Ron Vale iBioEducation Discovery Talk: Looking for Myosin and Finding Kinesin
- Carlos Bustamante iBioSeminar: Biochemistry in Singulo: When Less Means More
- Anthony Hyman iBioSeminar: Building a Polymer: Microtubule Dynamics
- Thomas Pollard: Cell Motility and Cytokinesis
Alberts, B. et al. (2002; 4th Edition). Molecular Biology of the Cell. Chapter 16. Garland Science. New York.
Vale, R. D. and Milligan, R. D. (2000). The way things move: looking under the hood of molecular motors. Science 288: 88-95.
Vale, R.D. (2003). The molecular motor toolbox for intracellular transport. Cell 112: 467-480.
Hirokawa N and Takemura R. (2005). Molecular motors and mechanisms of directional transport in neurons. Nat. Rev. Neurosci. 6:201-214.
Vallee, R.B., Williams, J.C., Varma, D., and Barnhart, L.E. (2004). Dynein: An ancient motor protein involved in multiple modes of transport. J. Neurobiol. 58:189-200.
Karsenti E. and Vernos I. (2001). The mitotic spindle: a self-made machine. Science 294:543-7.
Reck-Peterson, S.L., Yildiz, A., Carter, A.P., Gennerich, A., Zhang, N., and Vale, R.D. (2006). Stepping behavior and structural requirements for dynein processivity. Cell 126: 335-348.
Gennerich A, Carter AP, Reck-Peterson SL, Vale RD. (2007). Force-induced bidirectional stepping of cytoplasmic dynein. Cell 131:952-65.
Goshima G, Wollman R, Goodwin SS, Zhang N, Scholey JM, Vale RD, Stuurman N. (2007). Genes required for mitotic spindle assembly in Drosophila S2 cells. Science 316:417-21.
Burgess, S.A., Walker, M.L., Sakakibara, H., Knight, P.J., and Oiwa K. (2003). Dynein structure and power stroke. Nature 421:715-718.
Oiwa, K., and Sakakibara H. (2005). Recent progress in dynein structure and mechanism. Curr Opin Cell Biol. 17:98-103.
Bergnes, G., Brejc, K., and Belmont, L. (2005). Mitotic kinesins: prospects for antimitotic drug discovery. Curr. Top. Med. Chem. 5:127-145.
Marx, A., Muller, J., and Mandelkow E. (2005). The structure of microtubule motor proteins. Adv Protein Chem. 71:299-344.