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Publication Abstract from PubMed

Microtubules have spatiotemporally complex posttranslational modification patterns. Tubulin tyrosine ligase-like (TTLL) enzymes introduce the most prevalent modifications on alpha-tubulin and beta-tubulin. How TTLLs specialize for specific substrate recognition and ultimately modification-pattern generation is largely unknown. TTLL6, a glutamylase implicated in ciliopathies, preferentially modifies tubulin alpha-tails in microtubules. Cryo-electron microscopy, kinetic analysis and single-molecule biochemistry reveal an unprecedented quadrivalent recognition that ensures simultaneous readout of microtubule geometry and posttranslational modification status. By binding to a beta-tubulin subunit, TTLL6 modifies the alpha-tail of the longitudinally adjacent tubulin dimer. Spanning two tubulin dimers along and across protofilaments (PFs) ensures fidelity of recognition of both the alpha-tail and the microtubule. Moreover, TTLL6 reads out and is stimulated by glutamylation of the beta-tail of the laterally adjacent tubulin dimer, mediating crosstalk between alpha-tail and beta-tail. This positive feedback loop can generate localized microtubule glutamylation patterns. Our work uncovers general principles that generate tubulin chemical and topographic complexity.

Structural basis for alpha-tubulin-specific and modification state-dependent glutamylation.,Mahalingan KK, Grotjahn DA, Li Y, Lander GC, Zehr EA, Roll-Mecak A Nat Chem Biol. 2024 Apr 24. doi: 10.1038/s41589-024-01599-0. PMID:38658656^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.