Antonina I. Roll-Mecak
Mechanistic Dissection of the Tubulin Code
My lab is interested in understanding the interplay between microtubules and their regulators and how tubulin post-translational modifications tune the behavior of motors and microtubule associated proteins.
Microtubules are polymers essential for cell morphogenesis, cell division and intracellular transport. This polymer's basic building block is the alpha/beta tubulin heterodimer, which associates head-to-tail and laterally to form the microtubule. Microtubules execute their diverse cellular roles by forming suprastructures with highly distinctive geometries: the radial cytoplasmic array, the short, highly parallel axonemal array, the spindle array or the tiled long axonal array. The microtubule cytoskeleton is a complex function of many "unit operations", the individual actions of cytoskeletal regulators: nucleation, growth and shrinkage, severing and motor movement. Moreover, the microtubule itself is more than just a naive roadway for cellular components to transit along. Alpha and beta tubulins have multiple isoforms and are subject to highly diverse, abundant and evolutionarily conserved post-translational modifications that mark subpopulations of microtubules. Expansion of tubulin's genetic and post-translational repertoire coincides with increased metazoan complexity. The highest density and variety of post-translational modifications are found in especially complex microtubule arrays like those of neurons or cilia. Not surprisingly, many human diseases, including cancers, cardiovascular disease, fungal, bacterial and viral infections, and neurodegenerative disorders, are due to mutations in genes that encode microtubule dynamics regulators or in the tubulin genes themselves.
Is there a tubulin code written in the rich language of tubulin post-translational modifications and how does it provide specificity and regulation to cellular dynamics and trafficking of motor proteins and their cargo? My laboratory addresses this fundamental question by taking a comprehensive, multifaceted approach, linking atomic resolution information from our structural studies with single molecule dynamics in vitro and in the larger context of the cell. How functional diversity is imparted to different microtubules is a central question in cell biology. Our work aims to uncover the mechanistic underpinnings of the functions of microtubule chemical complexity in normal cellular function and disease.