Cellular division, wound healing, chemotaxis, and neuronal outgrowth all rely on dynamic shape change and adaptability afforded via an ever-changing cellular scaffold termed the cytoskeleton. We examine two core components of the cytoskeleton: microtubules and actin filaments in concert with the molecules that regulate them and facilitate communication between them. We employ a combined approach of high resolution time-dependent imaging in parallel with atomic resolution protein crystallography and cryo-electron microscopy to understand, at multiple scales, the molecular processes that control cytoskeletal dynamics. Of particular interest are the +TIP protein families that dynamically localize to growing microtubule plus ends where they regulate microtubule dynamics, communicate with the actin cytoskeleton, capture kinetochores, and engage the cell cortex under polarity-based cues. Investigations proceed through three key areas.
- Structure: Tertiary and quaternary molecular architecture of cytoskeletal regulators attained using x-ray crystallography and cryo-electron microscopy.
- Cellular and Organismal Imaging: Time-dependent systems analysis via genetic, opto-genetic, and small molecule manipulation.
- In Vitro Reconstitution: Microscopy-based physico-chemical analysis of cytoskeletal dynamics and convergent biological events (capture, signaling etc.) through titration of core components and regulators.
Interleaving these efforts, we aim to test, correlate, and bridge information gained from the organismal, cellular, sub-cellular and atomic levels. Of particular interest are the aberrant cytoskeletal molecular mechanisms at play in neuronal disorders and cancer biology.