Microtubules are polymers essential for cell morphogenesis, cell division and intracellular transport. They are subject to highly diverse, abundant and evolutionarily conserved post-translational modifications. Disruption of tubulin modification levels and patterns leads to cancers, neuropathologies and defective axonal regeneration. Our long-term goal is to understand how cells use tubulin isoform diversity and posttranslational modifications to regulate the structure and dynamics of microtubules as well as their interactions with molecular motors and microtubule associated proteins (MAPs). Although discovered over thirty years ago, an understanding of the roles of the chemical and genetic complexity of tubulin has remained elusive. My group integrates techniques and concepts from biophysics, proteomics, structural and cell biology to address this fundamental problem in microtubule cell biology. My laboratory has made significant progress towards these goals. These include: (1) development of novel methods for generating homogenous engineered single isoform recombinant unmodified human tubulin (Vemu et al., J. Biol. Chem., 2016); (2) determination of the first structure and dynamic instability parameters of recombinant isotopically pure recombinant neuronal tubulin (Vemu et al., J. Biol. Chem., 2016); (3) development of a biochemical platform for obtaining tubulin with quantitatively defined levels of posttranslational modifications (Valenstein and Roll-Mecak, Cell 2016) and use of this platform to (4) show the graded response of an important microtubule regulator, the hereditary spastic paraplegia protein spastin, to tubulin glutamylation (Valenstein and Roll-Mecak, Cell 2016) thus furnishing strong support for the tubulin code hypothesis. Our most recent work shows that microtubules with different isoform compositions exhibit dramatically different dynamic properties and that these properties can be proportionally tuned by varying tubulin isoform composition (Vemu et al., Mol. Biol. Cell, 2017). This indicates that the changes in isoform expression observed during morphogenesis and tumorigensis have a direct impact on microtubule dynamics and do not need to be mediated in trans through effectors. Using our platform for generating quantitatively defined modified microtubules as well recombinant engineered human microtubules, we will continue to interrogate how the tubulin code, both through genetic variation and posttranslational modifications, regulates the basic biophysical properties of microtubules as well as molecular motors and neuronal MAPs with strong involvement in neurodegenerative disorders.
| Pigino, Gaia; Roll-Mecak, Antonina (2017) Microtubule dynamics: 50 years after the discovery of tubulin and still going strong. Mol Biol Cell 28:705-706 |
| Vemu, Annapurna; Atherton, Joseph; Spector, Jeffrey O et al. (2017) Tubulin isoform composition tunes microtubule dynamics. Mol Biol Cell 28:3564-3572 |
| Sun, Xun; Park, James H; Gumerson, Jessica et al. (2016) Loss of RPGR glutamylation underlies the pathogenic mechanism of retinal dystrophy caused by TTLL5 mutations. Proc Natl Acad Sci U S A 113:E2925-34 |
| Valenstein, Max L; Roll-Mecak, Antonina (2016) Graded Control of Microtubule Severing by Tubulin Glutamylation. Cell 164:911-21 |
| Vemu, Annapurna; Atherton, Joseph; Spector, Jeffrey O et al. (2016) Structure and Dynamics of Single-isoform Recombinant Neuronal Human Tubulin. J Biol Chem 291:12907-15 |
