Antonina Roll-Mecak received her B.E in chemical engineering from the Cooper Union for the Advancement of Science and Art in 1996 and her Ph.D. in molecular biophysics from the Rockefeller University in 2002. She performed her postdoctoral work with Ron Vale at the University of California, San Francisco. She joined the NIH in 2010 as Chief of the Cell Biology and Biophysics Unit at the National Institute of Neurological Disorders and Stroke (NINDS) and investigator in the Biochemistry and Biophysics Center at the NHLBI. Dr. Roll-Mecak has received multiple honors for her work, including a Searle Scholar Award, a Burroughs Wellcome Career Award in the Biomedical Sciences, a NIH Pathway to Independence Award (K99), the L’Oréal-AAAS for Women in Science Fellowship, a Damon Runyon Cancer Research Postdoctoral Fellowship, and the Henry W. Reddick Fund Prize and Medal for meritorious work in Mathematics.
In addition to providing structural support, microtubules form a complex and dynamic intracellular “highway” that delivers molecular cargo from one end of the cell to another, which in the case of neuronal cells can span several feet. Given the continually changing cell physiology, this delivery system undergoes constant remodeling as cargo is transported to different destinations with high temporal and spatial accuracy. Failures in this highly coordinated transport system lead to disease and mutations in genes that encode microtubule dynamics regulators have been implicated in neurodegeneration, cardiovascular disease, cancers, and viral infections. Not surprisingly, tubulin, the building block of the microtubule network is one of the most post-translationally modified proteins in the cell. Dr. Roll-Mecak’s laboratory combines biophysical and cell biological approaches to understand the interplay between microtubules and their regulators and how tubulin post-translational modifications tune the behavior of motors and microtubule associated proteins.
The Roll-Mecak laboratory currently focuses on two main topics with translational potential:
Mechanism of microtubule severing enzymes. Microtubule severing enzymes can shorten long microtubules or release them from their nucleation site, but in so doing can also provide new ends that can serve as the nuclei for building new polymers. What is the mechanism of action of microtubule severing enzymes? How are their enzymatic activities regulated and spatially restricted? Her group is currently concentrating its efforts on the mechanism of microtubule severing by spastin, a protein mutated in 40% of patients with hereditary spastic paraplegia.
Mechanism of tubulin modification enzymes and consequences of these modifications on microtubule behavior. Tubulin is subject to abundant and diverse post-translational modifications that includes phosphorylation, acetylation, poly-glutamylation and detyrosination/tyrosination. Dr. Roll-Mecak’s group employs X-ray crystallography, small angle X-ray scattering, classical kinetics, and high-resolution fluorescence techniques to understand the mechanism of the enzymes that add these diverse modifications as well as how these modifications modulate the dynamics and mechanical properties of microtubules. Her group solved the first crystal structure of tubulin tyrosine ligase and helped elucidate the mechanism used by this enzyme to recognize tubulin. Recent work from her group also shed light on the structure and mechanism of action of tubulin acetyltransferase, an unusual enzyme that acetylates a site that is situated inside the microtubule lumen.
Despite the abundance and complexity of tubulin modifications, their effects on microtubule behavior are still poorly understood. Is the microtubule more than just a structural strut, or a naive roadway for cellular components to transit along? Is there a "tubulin code", written in the rich language of the post-translational modifications of tubulin that, much like a histone code, provides specificity and regulation to cellular dynamics and to the trafficking of motor proteins and their cargo on the cellular highway? How functional diversity is imparted to different microtubules is a central question in cell biology with important implications for human health.
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