6VZS

Engineered TTLL6 mutant bound to gamma-elongation analog

6VZS の概要

• エントリーDOI: 10.2210/pdb6vzs/pdb
• 分子名称: Tubulin polyglutamylase TTLL6, ADENOSINE-5'-DIPHOSPHATE, (2~{S})-2-[[[(3~{R})-3-acetamido-4-oxidanyl-4-oxidanylidene-butyl]-phosphonooxy-phosphoryl]methyl]pentanedioic acid, ... (6 entities in total)
• 機能のキーワード: protein engineering, ttll6, glutamylation, amino-acid ligase, ligase
• 由来する生物種: Mus musculus (Mouse)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 220056.91

構造登録者

Mahalingan, K.K.,Keenen, E.K.,Strickland, M.,Li, Y.,Liu, Y.,Ball, H.L.,Tanner, M.E.,Tjandra, N.,Roll-Mecak, A. (登録日: 2020-02-28, 公開日: 2020-08-12, 最終更新日: 2023-10-11)

主引用文献

Mahalingan, K.K.,Keith Keenan, E.,Strickland, M.,Li, Y.,Liu, Y.,Ball, H.L.,Tanner, M.E.,Tjandra, N.,Roll-Mecak, A.
Structural basis for polyglutamate chain initiation and elongation by TTLL family enzymes.
Nat.Struct.Mol.Biol., 27:802-813, 2020

PubMed Abstract: Glutamylation, introduced by tubulin tyrosine ligase-like (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 post-translationally add glutamates to internal glutamates in tubulin carboxy-terminal tails (branch initiation, through an isopeptide bond), and additional glutamates can extend these (elongation). TTLLs are thought to specialize in 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 enzyme 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 post-translationally 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.

PubMed: 32747782
DOI: 10.1038/s41594-020-0462-0

実験手法

X-RAY DIFFRACTION (2.66 Å)