Jonathon Howard - Mechanics of motor proteins and the cytoskeleton

Previous and current research

Our laboratory is interested in the biochemical and biophysical basis of cell shape and motion. The shape of a cell is determined primarily by its cytoskeleton, which serves as a scaffold to support the plasma membrane and internal organelles. The cytoskeleton also serves a network of tracks along which motor proteins transport subcellular structures. Our research is therefore focused on the mechanics of the cytoskeleton, with a particular emphasis on microtubules and microtubule-based motor proteins.

On one hand, we are interested in the mechanisms by which these proteins work: i.e. how do kinesins and dyneins act as molecular machines to convert chemical energy derived from the hydrolysis of ATP into mechanical work used to move along or to depolymerize microtubules? And on the other hand, we are interested in the roles that microtubules and their motors play in cell morphology and motility. For example, how do the dynamic properties of microtubules drive spindle and chromosome movements in mitosis, and how does dynein drive axonemal motility? What roles do microtubules and their motors play in mechanoreception in sensory cells and in determining the shapes of cells? What makes these problems so fascinating is that somehow molecules, whose dimension is on the order of nanometers, coordinate the assembly or movement of structures whose dimension is on the order of the size of the cell, some thousand to million times larger than molecular dimensions. The key to answering these questions is to characterize the interactions between the individual molecules in vitro, to use theory to understand how these interactions lead to the collective behavior of the ensemble of molecules, and then to test these models with in vivo experiments.

To address these issues, we are combining molecular biology techniques with single-molecule recordings, image processing, modeling, mechanical measurements, and electron microscopy. Our work benefits from close collaborations with physicists from the MPI for the Physics of Complex Systems.

Processive motility of the depolymerase kinesin-8 (green) along microtubules (red). The speed is ~3 microns per minute.

Future prospects and goals

To use single-molecule techniques to determine how depolymerases (such as the kinesin-related proteins MCAK and Kip3p) and polymerases (such as XMAP215) influence microtubule dynamics.
To use optical tweezers to measure molecular forces during microtubule depolymerization in vitro and in vivo in the early embryo of the worm.
To use physiological, genetic and single-molecule tools together with electron microscopic tomography to elucidate the molecular basis of transduction in microtubule-based mechanoreceptors.
To understand the molecular interactions that underlie complex dynamical processes such as the beating of sperm and cilia and the positioning of mitotic spindles.
To gauge the relative mechanical contributions of the cell membrane and the cytoskeleton to the establishment and mainatinance of cell shape using various blood cells as models.

Selected publications

Pecreaux, J., Röper, J.-C., Kruse, K., Julicher, K., Hyman, A.A., Grill, S.W., Howard, J. (2006): Spindle oscillations during asymmetric cell division require a threshold number of active cortical force generators. Curr. Biol. 16: 2111-2122.

Varga, V., Helenius, J., Hyman, A.A., Tanaka, K., Tanaka, T. & Howard, J. (2006): The yeast kinesin-8 Kip3p is a highly processive motor that depolymerizes microtubules in a length-dependent manner. Nat. Cell Biol. 8: 957-962.

Helenius, J., Brouhard, G., Kalaidzidis, Y., Diez, S. & Howard, J. (2006): The depolymerizing kinesin MCAK uses 1-Dimensional diffusion to rapidly target microtubule ends. Nature 441: 115-119.

Riedel, I.H., Kruse, K. & Howard, J. (2005): A self-organized vortex array of hydrodynamically entrained sperm cells. Science 309:300-303.

Howard, J. & Bechstedt, S. (2004): Hypothesis: a helix of ankyrin repeats of the NOMPC-TRP ion channel is the gating spring of mechanoreceptors. Current Biol. 14: R224-226.

Jonathon Howard

1983: PhD in Neuro-biology, Australian National University, Canberra

1985-1987: Postdoctoral Fellow, Dept of Physiology, UC San Francisco

1988-1989: Assistant Research Physiologist, University of California, San Francisco

1989-1994: Assistant Professor, Dept of Physiology & Biophysics, U.W.

1994-1997: Associate Professor, Dept of Physiology & Biophysics, U.W.

1997-2001: Professor, Dept of Physiology & Biophysics, University of Washington

since 2000: Director, Max Planck Institute for Molecular Cell Biology and Genetics, Dresden

since 2001: Honorary Professor, Dresden University of Technology