Journal
EMBO REPORTS
Volume 18, Issue 6, Pages 1013-1026Publisher
WILEY
DOI: 10.15252/embr.201643751
Keywords
glutamylases; microtubules; molecular dynamics; TTLLs; tubulin code
Categories
Funding
- programme Investissements d'Avenir [ANR-10-LBX-0038, ANR-10-IDEX-0001-02 PSL*]
- FRM fellowship [SPF20140129173, SPF20120523942]
- EMBO [ALTF 638-2010, ASTF 445-2012]
- [ANR-12-BSV2-0007]
- [INCA 2013-1-PLBIO-02-ICR-1]
- [2014-PLBIO-11-ICR-1]
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Posttranslational modifications of tubulin currently emerge as key regulators of microtubule functions. Polyglutamylation generates a variety of modification patterns that are essential for controlling microtubule functions in different cell types and organelles, and deregulation of these patterns has been linked to ciliopathies, cancer and neurodegeneration. How the different glutamylating enzymes determine precise modification patterns has so far remained elusive. Using computational modelling, molecular dynamics simulations and mutational analyses we now show how the carboxy-terminal tails of tubulin bind into the active sites of glutamylases. Our models suggest that the glutamylation sites on - and -tubulins are determined by the positioning of the tails within the catalytic pocket. Moreover, we found that the binding modes of - and -tubulin tails are highly similar, implying that most enzymes could potentially modify both, - and -tubulin. This supports a model in which the binding of the enzymes to the entire microtubule lattice, but not the specificity of the C-terminal tubulin tails to their active sites, determines the catalytic specificities of glutamylases.
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