6vzu

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TTLL6 bound to alpha-elongation analogTTLL6 bound to alpha-elongation analog

Structural highlights

6vzu is a 6 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 1.98Å
Ligands:, , , , ,
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).[1] [2] [3] [4] [5] [6] [7]

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[8]

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

References

  1. ↑ van Dijk J, Rogowski K, Miro J, Lacroix B, Eddé B, Janke C. A targeted multienzyme mechanism for selective microtubule polyglutamylation. Mol Cell. 2007 May 11;26(3):437-48. PMID:17499049 doi:10.1016/j.molcel.2007.04.012
  2. ↑ Lacroix B, van Dijk J, Gold ND, Guizetti J, Aldrian-Herrada G, Rogowski K, Gerlich DW, Janke C. Tubulin polyglutamylation stimulates spastin-mediated microtubule severing. J Cell Biol. 2010 Jun 14;189(6):945-54. PMID:20530212 doi:10.1083/jcb.201001024
  3. ↑ Rogowski K, van Dijk J, Magiera MM, Bosc C, Deloulme JC, Bosson A, Peris L, Gold ND, Lacroix B, Bosch Grau M, Bec N, Larroque C, Desagher S, Holzer M, Andrieux A, Moutin MJ, Janke C. A family of protein-deglutamylating enzymes associated with neurodegeneration. Cell. 2010 Nov 12;143(4):564-78. PMID:21074048 doi:10.1016/j.cell.2010.10.014
  4. ↑ Lee JE, Silhavy JL, Zaki MS, Schroth J, Bielas SL, Marsh SE, Olvera J, Brancati F, Iannicelli M, Ikegami K, Schlossman AM, Merriman B, Attié-Bitach T, Logan CV, Glass IA, Cluckey A, Louie CM, Lee JH, Raynes HR, Rapin I, Castroviejo IP, Setou M, Barbot C, Boltshauser E, Nelson SF, Hildebrandt F, Johnson CA, Doherty DA, Valente EM, Gleeson JG. CEP41 is mutated in Joubert syndrome and is required for tubulin glutamylation at the cilium. Nat Genet. 2012 Jan 15;44(2):193-9. PMID:22246503 doi:10.1038/ng.1078
  5. ↑ Bosch Grau M, Gonzalez Curto G, Rocha C, Magiera MM, Marques Sousa P, Giordano T, Spassky N, Janke C. Tubulin glycylases and glutamylases have distinct functions in stabilization and motility of ependymal cilia. J Cell Biol. 2013 Aug 5;202(3):441-51. PMID:23897886 doi:10.1083/jcb.201305041
  6. ↑ Xia P, Ye B, Wang S, Zhu X, Du Y, Xiong Z, Tian Y, Fan Z. Glutamylation of the DNA sensor cGAS regulates its binding and synthase activity in antiviral immunity. Nat Immunol. 2016 Apr;17(4):369-78. PMID:26829768 doi:10.1038/ni.3356
  7. ↑ Mahalingan KK, Keith Keenan E, Strickland M, Li Y, Liu Y, Ball HL, Tanner ME, Tjandra N, Roll-Mecak A. Structural basis for polyglutamate chain initiation and elongation by TTLL family enzymes. Nat Struct Mol Biol. 2020 Sep;27(9):802-813. PMID:32747782 doi:10.1038/s41594-020-0462-0
  8. ↑ Mahalingan KK, Keith Keenan E, Strickland M, Li Y, Liu Y, Ball HL, Tanner ME, Tjandra N, Roll-Mecak A. Structural basis for polyglutamate chain initiation and elongation by TTLL family enzymes. Nat Struct Mol Biol. 2020 Sep;27(9):802-813. PMID:32747782 doi:10.1038/s41594-020-0462-0

6vzu, resolution 1.98Å

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