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229 Hallowell Building
University Park, PA 16802
Phone: 814-863-0492 / Fax: 814-863-0490
Hancock Lab Website: http://www.bioe.psu.edu/labs/Hancock-Lab/index.html
Ph.D. Bioengineering University of Washington, Seattle, 1994
The intracellular environment is a very dynamic place, with organelles and vesicles moving to and fro and material being transported to various regions of the cell. The molecules responsible for this movement are motor proteins, which use chemical energy to move along cytoskeletal tracks. The focus of my lab is to understand the detailed workings of motor proteins and their role in intracellular transport, cell motility and cell division.
We concentrate on the kinesin superfamily of microtubule-based motors, which are involved in a broad array of cellular processes including axonal transport, the positioning of intracellular organelles, and the movement of chromosomes during meiosis and mitosis. Kinesins share a ~340 amino acid motor domain (the head), and members of the family utilize the motor domain in various ways - to move towards the plus- or minus-ends of microtubules (towards the cell periphery or center, respectively), or even to depolymerize microtubules.
Kinesins are especially interesting because they lie at the interface of biochemistry and mechanics at the level of a single protein molecule. To study these motors we are using the tools of modern molecular biology to isolate and express specific domains of the motors, and then using a two-pronged attack of single-molecule motility measurements and computational modeling to analyze the biochemical and mechanical function of these mutant motors. We are especially interested in Kinesin-2 motors (also called KIF3A/B), which are involved in intraflagellar transport, among other tasks. These motors are distinctive because they contain two different motor domains instead of the usual homodimeric configuration. Our current efforts are aimed at understanding the role of the neck linker domain in transmitting mechanical signals between the two motor domains. This mechanical communication is the signal by which the two motor domains coordinate their activities to walk long distances along microtubules. Insights into mechanisms by which mechanical forces alter biochemical rate constants are relevant to understanding cell adhesion and mechanotransduction, among other physiological processes.
In addition to these fundamental experiments, we are working together with colleagues in Chemistry, Electrical Engineering and Biochemistry and Molecular Biology to integrate kinesin motors and microtubules into microfabricated devices and interface these proteins with nanoparticles and novel materials. The initial goal of this work was to develop microfluidic devices for analyte detection and molecular sorting that use kinesin-driven transport instead of pressure-driven flow. Our current focus is on developing microscale and nanoscale tools to investigate the role of kinesins and microtubules in cell division and the maintenance of proper microtubule polarity in growing neurons. These fundamental investigations are important for understanding the rapid cell proliferation underlying cancer and in envisioning novel approaches to treat neural regeneration following injury.
The eventual goal of this work is to better understand the role of kinesin motors in normal and diseased states, to define targets for future therapeutics, and to establish a building blocks for future nano-scale diagnostic or therapeutic devices.
"Artificial Mitotic Spindle" generated by dielectrophoresis and protein micropatterning supports bidirectional transport of kinesin-coated beads. M. Uppalapati, Y.-M. Huang, V. Aravamuthan, T.N. Jackson and W.O. Hancock. 2011. Integrative Biology 3:57-64.
Neck linker length determines the degree of processivity in Kinesin-1 and Kinesin-2 motors. S. Shastry and W.O. Hancock. 2010. Current Biology 20: 939-943.
Monte Carlo analysis of neck linker extension in kinesin molecular motors. M..L Kutys, J. Fricks and W.O. Hancock. 2010. PLoS Computational Biology 6(11): e1000980. doi:10.1371/journal.pcbi.1000980.
The Processivity of Kinesin-2 Motors Suggests Diminished Front-Head Gating. G. Muthukrishnan, Y. Zhang, S. Shastry and W.O. Hancock. 2009. Current Biology 19(5):442-7.
Insights into the mechanical properties of the kinesin neck linker domain from sequence analysis and molecular dynamics simulations. V. Hariharan and W.O. Hancock. 2009. Cellular and Molecular Bioengineering 2(2):177-89.
Microtubule alignment and manipulation using AC electrokinetics. M. Uppalapati, Y. M. Huang, T.N. Jackson and W.O. Hancock. 2008. Small 4(9): 1371-81.
Microtubule transport, concentration and alignment in enclosed microfluidic channels. Y.-M. Huang, M. Uppalapati, W.O. Hancock and T.N. Jackson. 2007. Biomedical Microdevices 9:175-184.