5
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: not found
      • Article: not found

      Structural basis for polyglutamate chain initiation and elongation by TTLL family enzymes

      Read this article at

      ScienceOpenPublisherPubMed
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Related collections

          Most cited references40

          • Record: found
          • Abstract: found
          • Article: not found

          A targeted multienzyme mechanism for selective microtubule polyglutamylation.

          Polyglutamylases are enzymes that form polyglutamate side chains of variable lengths on proteins. Polyglutamylation of tubulin is believed to regulate interactions of microtubules (MTs) with MT-associated proteins and molecular motors. Subpopulations of MTs are differentially polyglutamylated, yet only one modifying enzyme has been discovered in mammals. In an attempt to better understand the heterogeneous appearance of tubulin polyglutamylation, we searched for additional enzymes and report here the identification of six mammalian polyglutamylases. Each of them has a characteristic mode of catalysis and generates distinct patterns of modification on MTs, which can be further diversified by cooperation of multiple enzymes. Polyglutamylases are restricted to confined tissues and subtypes of MTs by differential expression and localization. In conclusion, we propose a multienzyme mechanism of polyglutamylation that can explain how the diversity of polyglutamylation on selected types of MTs is controlled at the molecular level.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Tubulin post-translational modifications: encoding functions on the neuronal microtubule cytoskeleton.

            In the past decades, a range of post-translational modifications has been discovered on tubulins, the major constituents of microtubules. Pioneering studies have described the occurrence and dynamics of these modifications and provided first insights into their potential functions in regulating the microtubule cytoskeleton. By contrast, several tubulin-modifying enzymes were only discovered in the last few years, and studies on molecular mechanisms and cellular functions of tubulin modifications are just beginning to emerge. This review highlights the roles of tubulin modifications in neurons. Recent studies are also discussed in relation to how the combinatorial use of tubulin modifications could generate a dynamic microtubule code, and how such a code might regulate basic as well as higher-order neuronal functions. Copyright 2010 Elsevier Ltd. All rights reserved.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Amyloid-β oligomers induce synaptic damage via Tau-dependent microtubule severing by TTLL6 and spastin.

              Mislocalization and aggregation of Aβ and Tau combined with loss of synapses and microtubules (MTs) are hallmarks of Alzheimer disease. We exposed mature primary neurons to Aβ oligomers and analysed changes in the Tau/MT system. MT breakdown occurs in dendrites invaded by Tau (Tau missorting) and is mediated by spastin, an MT-severing enzyme. Spastin is recruited by MT polyglutamylation, induced by Tau missorting triggered translocalization of TTLL6 (Tubulin-Tyrosine-Ligase-Like-6) into dendrites. Consequences are spine loss and mitochondria and neurofilament mislocalization. Missorted Tau is not axonally derived, as shown by axonal retention of photoconvertible Dendra2-Tau, but newly synthesized. Recovery from Aβ insult occurs after Aβ oligomers lose their toxicity and requires the kinase MARK (Microtubule-Affinity-Regulating-Kinase). In neurons derived from Tau-knockout mice, MTs and synapses are resistant to Aβ toxicity because TTLL6 mislocalization and MT polyglutamylation are prevented; hence no spastin recruitment and no MT breakdown occur, enabling faster recovery. Reintroduction of Tau re-establishes Aβ-induced toxicity in TauKO neurons, which requires phosphorylation of Tau's KXGS motifs. Transgenic mice overexpressing Tau show TTLL6 translocalization into dendrites and decreased MT stability. The results provide a rationale for MT stabilization as a therapeutic approach.
                Bookmark

                Author and article information

                Contributors
                (View ORCID Profile)
                (View ORCID Profile)
                (View ORCID Profile)
                (View ORCID Profile)
                (View ORCID Profile)
                Journal
                Nature Structural & Molecular Biology
                Nat Struct Mol Biol
                Springer Science and Business Media LLC
                1545-9993
                1545-9985
                August 3 2020
                Article
                10.1038/s41594-020-0462-0
                32747782
                7f6253ca-1b82-4368-84a4-fe0f98adb127
                © 2020

                http://www.springer.com/tdm

                http://www.springer.com/tdm

                History

                Comments

                Comment on this article

                scite_
                0
                0
                0
                0
                Smart Citations
                0
                0
                0
                0
                Citing PublicationsSupportingMentioningContrasting
                View Citations

                See how this article has been cited at scite.ai

                scite shows how a scientific paper has been cited by providing the context of the citation, a classification describing whether it supports, mentions, or contrasts the cited claim, and a label indicating in which section the citation was made.

                Similar content1,014

                Cited by21

                Most referenced authors925