6vzq | pdb_00006vzq

Engineered TTLL6 mutant bound to alpha-elongation analog

spinqualitylabelsall models 6vzq, resolution 3.08Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6vzq is a 4 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3.08Å Ligands: ADP, GOL, MG, RZP, RZY Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function TTLL6_MOUSE Polyglutamylase which modifies both tubulin and non-tubulin proteins, generating alpha-linked polyglutamate side chains on the gamma-carboxyl group of specific glutamate residues of target proteins (PubMed:17499049, PubMed:21074048, PubMed:20530212, PubMed:26829768, PubMed:32747782). Preferentially mediates ATP-dependent long polyglutamate chain elongation over the initiation step of the polyglutamylation reaction (PubMed:17499049, PubMed:21074048, PubMed:20530212, PubMed:26829768, PubMed:32747782). Preferentially modifies the alpha-tubulin tail over a beta-tail (PubMed:17499049, PubMed:20530212, PubMed:21074048, PubMed:32747782). Promotes tubulin polyglutamylation which stimulates spastin/SPAST-mediated microtubule severing, thereby regulating microtubule functions (PubMed:20530212). Mediates microtubule polyglutamylation in primary cilia axoneme which is important for ciliary structural formation and motility (PubMed:22246503). Mediates microtubule polyglutamylation in motile cilia, necessary for the regulation of ciliary coordinated beating (PubMed:23897886). Polyglutamylates non-tubulin protein nucleotidyltransferase CGAS, leading to CGAS DNA-binding inhibition, thereby preventing antiviral defense response (PubMed:26829768). Publication Abstract from PubMed 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. Structural basis for polyglutamate chain initiation and elongation by TTLL family enzymes.,Mahalingan KK, Keith Keenan E, Strickland M, Li Y, Liu Y, Ball HL, Tanner ME, Tjandra N, Roll-Mecak A Nat Struct Mol Biol. 2020 Sep;27(9):802-813. doi: 10.1038/s41594-020-0462-0. Epub , 2020 Aug 3. PMID:32747782 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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