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THE TUBULIN CODE: Deciphering and Engineering the Chemical and Genetic Complexity of the Microtubule Cytoskeleton

Cells depend on the asymmetric distribution of their components for homeostasis, differentiation and movement. In no other cell type is this requirement more critical than in the neuron where complex structures are generated during process growth and elaboration and cargo is transported over distances several thousand times the cell body diameter. Microtubules are essential polymers that act both as dynamic structural elements and as tracks for intracellular transport. The fundamental question that we are pursuing is: how is specificity encoded and asymmetry generated in the microtubule network?

Deceptively uniform ultrastructurally, microtubules bear a bewildering range of reversible posttranslational modifications, including acetylation, detyrosination, phosphorylation, glutamylation and glycylation.  These vary widely between cell types and their patterns are stereotyped. This is suggestive of temporally and spatially regulated control of microtubule effectors and dynamics. Such regulation would have parallels with the histone code. Disruption of tubulin modification levels and patterns leads to cancers, neuropathologies and defective axonal regeneration.  Although discovered over thirty years ago, an understanding of the roles of the chemical complexity of microtubules has remained elusive. 

My laboratory aims to understand (1) the biochemical mechanisms of tubulin modification enzymes and how the complex patterns of tubulin posttranslational modifications observed in cells are generated by these enzyme families  (2) the effects of tubulin posttranslational modifications on the basic properties of the microtubule polymer: its mechanical properties and dynamics and (3) the effects of tubulin modifications on the recruitment and function of cellular effectors.

What approaches do we use?

X-ray crystallography SAXS EM Protein Engineering Single Molecule Fluorescence Live Cell Imaging

We take a multifaceted experimental approach to answer these questions, integrating atomic resolution information on cytoskeletal regulators with single molecule dynamics in vitro and the larger context of the cell. We combine X-ray crystallography, small angle X-ray scattering and electron microscopy to obtain high-resolution snapshots of these tiny protein machines in action. Classic enzymology as well as high-resolution fluorescence microscopy and spectroscopy techniques are employed to understand the dynamic behavior of these molecular machines and the knowledge of their fundamental properties garnered from these in vitro studies is used at the cellular level.

Who does the research?

The lab welcomes biologists, chemists, physicists and engineers who are interested in joining our interdisciplinary efforts to crack the tubulin code