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Molecular basis for age-dependent microtubule acetylation by tubulin acetyltransferase

TitleMolecular basis for age-dependent microtubule acetylation by tubulin acetyltransferase
Publication TypeJournal Article
Year of Publication2014
AuthorsSzyk, A, Deaconescu AM, Spector J, Goodman B, Valenstein ML, Ziolkowska NE, Kormendi V, Grigorieff N, Roll-Mecak A
Refereed DesignationRefereed

Microtubule acetylation by tubulin acetyltransferase (TAT) is the only known posttranslational modification of the microtubule lumen. It marks stable microtubules on α-tubulin Lys40 and is required for polarity establishment and directional migration. Here we elucidate the mechanistic underpinnings for TAT activity and its preference for microtubules with slow turnover. A 1.35 Å TAT cocrystal structure constrains TAT action to the microtubule lumen and reveals Lys40 engaged in a suboptimal active site. Assays with diverse tubulin polymers demonstrate that TAT is stimulated by inter-protofilament contacts in microtubules. Unexpectedly, despite the confined intraluminal location of Lys40, the enzyme efficiently scans the microtubule bidirectionally and acetylates stochastically without a preference for ends. First-principles modeling and single-molecule diffusion measurements demonstrate that TAT catalytic activity, not constrained luminal diffusion, is rate-limiting for acetylation. Thus, because of its preference for microtubules over free tubulin and its modest catalytic rate, TAT can function as a slow clock for microtubule lifetimes.

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