Structural basis for polyglutamate chain initiation and elongation by TTLL family enzymes
Kishore K Mahalingan,
E. Keith Keenen,
Haydn L Ball,
Martin E Tanner,
Posted 08 Jun 2020
bioRxiv DOI: 10.1101/2020.06.07.139295 (published DOI: 10.1038/s41594-020-0462-0)
Posted 08 Jun 2020
Glutamylation, introduced by TTLL enzymes, is the most abundant modification of brain tubulin. Essential effector proteins read the tubulin glutamylation pattern, and its misregulation causes neurodegeneration. TTLL glutamylases posttranslationally add glutamates to internal glutamates in tubulin C-terminal tails (branch initiation, through an isopeptide bond), and additional glutamates can extend these (elongation). TTLLs are thought to specialize for initiation or elongation, but the mechanistic basis for regioselectivity is unknown. We present cocrystal structures of murine TTLL6 bound to tetrahedral intermediate analogs that delineate key active-site residues that make this an elongase. We show that TTLL4 is exclusively an initiase, and through combined structural and phylogenetic analyses, engineer TTLL6 into a branch-initiating enzyme. TTLL glycylases add glycines posttranslationally to internal glutamates, and we find that the same active-site residues discriminate between initiase and elongase glycylases. These active-site specializations of TTLL glutamylases and glycylases ultimately yield the chemical complexity of cellular microtubules. ### Competing Interest Statement The authors have declared no competing interest.
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