Molecular Mechanisms of Cytoskeletal Form & Function

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 to understand, at multiple scales, the molecular processes that control cytoskeletal dynamics. Of particular interest are the +TIP proteins that regulate microtubule plus end dynamics, regulators of centriole duplication and structure, factors that coordinate microtubule and actin dynamics, and regulators of the dynein motor complex. Mechanistic investigations examine cytoskeletal protein function via:

1. Structure: Tertiary and quaternary molecular architecture of cytoskeletal regulators attained using x-ray crystallography.
2. Cellular & Organismal Imaging: Time-dependent systems analysis via genetic and small molecule manipulation.
3. 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 tissue, cellular, sub-cellular, and atomic levels. Of particular interest are the aberrant cytoskeletal molecular mechanisms that underlie ciliopathies, neuropathies, and cancer.

© Kevin Slep