Part III: Regulation of Mammalian Dynein
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|iBiology Archives: Ron Vale iBioSeminar (2007)|
Molecular motor proteins are fascinating enzymes that power much of the movement performed by living organisms. In this introductory 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 talk first describes the broad spectrum of biological roles that kinesin, dynein and myosin play in cells. The talk then discusses how these nanoscale proteins convert energy from ATP hydrolysis into unidirectional motion and force production, and compares common principles of kinesin and myosin. The talk concludes by discussing the role of motor proteins in disease and how drugs that modulate motor protein activity can treat human disease.
Part 2 discusses recent work from the Vale laboratory and other groups, on the mechanism of movement by dynein, a microtubule motor that is less well understood than kinesin and myosin. The lecture discusses the unusual properties of dynein stepping along microtubules, which have been uncovered using single molecule techniques. The nucleotide-driven structural changes in the dynein motor domain (elucidated by X-ray crystallography and electron microscopy) are also described. A model for dynein movement in the form of an animation is presented. However, much remains to be done in order to understand how this motor works and to test which elements of this model are correct.
The third (last) part of the lecture explains how the movement of mammalian dynein is regulated by other proteins such dynactin and adapter proteins. It also describes the effect of post-translational modifications of tubulin on dynein motility. This talk features the use of single molecule imaging techniques and biochemical reconstitution to study these problems. Unanswered questions on dynein regulation are also presented.
This video was produced in collaboration with the Lasker Foundation.
Ron Vale is a Professor of Cellular and Molecular Pharmacology at the University of California, San Francisco and an Investigator of the Howard Hughes Medical Institute. He is also the founder of the iBiology project.
Vale received a B.A. degree in biology and chemistry from the University of California, Santa Barbara, and a Ph.D. degree in neuroscience from Stanford University. 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 Lasker Award for Basic Medical Research, and elections to the National Academy of Sciences, National Academy of Medicine, and the American Academy of Arts and Sciences. Besides studying the mechanism of motor proteins, Vale’s laboratory studies mitosis, RNA biology, and the mechanism of T cell signaling.
- 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
Vale, R. D. and Milligan, R.A. (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.
Malik FI, Hartman JJ, Elias KA, Morgan BP, Rodriguez H, Brejc K, Anderson RL, Sueoka SH, Lee KH, Finer JT, Sakowicz R, Baliga R, Cox DR, Garard M, Godinez G, Kawas R, Kraynack E, Lenzi D, Lu PP, Muci A, Niu C, Qian X, Pierce DW, Pokrovskii M, Suehiro I, Sylvester S, Tochimoto T, Valdez C, Wang W, Katori T, Kass DA, Shen YT, Vatner SF, Morgans DJ. (2011) Cardiac myosin activation: a potential therapeutic approach for systolic heart failure. Science. Mar 18;331(6023):1439-43.
Nakamura M, Chen L, Howes SC, Schindler TD, Nogales E, Bryant Z. (2014) Remote control of myosin and kinesin motors using light-activated gearshifting. Nat Nanotechnol. Sep;9(9):693-7.
Part 2: Bhahbha, G., Cheng, H.-C., Zhang, N., Moeller, A., Liao, M., Speir, J.A., Cheng, Y., and Vale, R.D. (2014). Allosteric communication in the dynein motor domain. Cell 159:857-868.
Bhahba, G., Johnson, G.T., Schroeder, C. and Vale, R.D. (2016). How dynein moves along microtubules. Trends BIol. Chem. 41:94-105.
Part 3: McKenney, R.J., Huynh, W., Tanenbaum, M. E., Bhabha, G., and Vale, R.D. (2014). Activation of cytoplasmic dynein motility by dynactin-cargo adapter complexes. Science 345:337-341.
Urnavicius L, Zhang K, Diamant AG, Motz C, Schlager MA, Yu M, Patel NA, Robinson CV, Carter AP.(2015) The structure of the dynactin complex and its interaction with dynein. Science. Mar 27;347(6229):1441-6
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.