Transglutaminase and Polyamination of Tubulin: Posttranslational Modification for Stabilizing Axonal Microtubules

Song, Yuyu; Kirkpatrick, Laura L.; Schilling, Alexander; Helseth, Donald L.; Chabot, Nicolas; Keillor, Jeffrey W.; Johnson, Gail V.W.; Brady, Scott T.

doi:10.1016/j.neuron.2013.01.036

Cited by 179 publications

(206 citation statements)

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“…Tubulin posttranslational modifications are chemically diverse, ranging from phosphorylation (17), acetylation (18,19), palmitoylation (20), sumoylation (21), polyamination (22), and S-nitrosylation (23) to tyrosination (24), glutamylation (25,26), and glycylation (27). Most of these modifications are reversible.…”

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confidence: 99%

Writing and Reading the Tubulin Code

Garnham

Roll-Mecak

2015

Journal of Biological Chemistry

179

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Microtubules give rise to intracellular structures with diverse morphologies and dynamics that are crucial for cell division, motility, and differentiation. They are decorated with abundant and chemically diverse posttranslational modifications that modulate their stability and interactions with cellular regulators. These modifications are important for the biogenesis and maintenance of complex microtubule arrays such as those found in spindles, cilia, neuronal processes, and platelets. Here we discuss the nature and subcellular distribution of these posttranslational marks whose patterns have been proposed to constitute a tubulin code that is interpreted by cellular effectors. We review the enzymes responsible for writing the tubulin code, explore their functional consequences, and identify outstanding challenges in deciphering the tubulin code.Microtubules are non-covalent cylindrical polymers formed by ␣␤-tubulin heterodimer building blocks. They possess two seemingly contradictory properties; they are highly dynamic, exhibiting rapid growth and shrinkage of their ends (1), but are also very rigid, with persistence lengths on the order of cellular dimensions (2). This duality is thought to underlie the versatile architectures of microtubule networks in cells ( Fig. 1) and is tuned by a myriad of cellular effectors. These fall into two categories: effectors that bind to the microtubule and alter its properties non-covalently (motors and microtubule-associated proteins (MAPs)) 2 and effectors that chemically modify the tubulin subunits (tubulin posttranslational modification enzymes). Although the field has made tremendous progress in recent decades identifying a compendium of microtubule-interacting proteins and understanding their interplay and regulation in the cell, we are just now starting to unravel the basic mechanisms used by cells to chemically modify microtubules, despite the fact that tubulin posttranslational modifications have been known for over 40 years. A renaissance of interest into the roles of tubulin posttranslational modifications has been precipitated by the discovery in the last few years of the enzymes responsible for these modifications (3-8), methods for producing unmodified (9, 10), engineered, (11, 12) as well as chemically defined modified tubulin (13), and developments and refinements of in vitro microtubule-based assays using high-resolution microscopy and microfabricated substrates (14 -16).Tubulin posttranslational modifications are chemically diverse, ranging from phosphorylation (17), acetylation (18,19), palmitoylation (20), sumoylation (21), polyamination (22), and S-nitrosylation (23) to tyrosination (24), glutamylation (25, 26), and glycylation (27). Most of these modifications are reversible. Tubulin posttranslational modifications are evolutionarily conserved and abundantly represented in cellular microtubules. Most importantly, their distribution is stereotyped in cells. For example, interphase microtubules are enriched in tyrosination (28), whereas kinetochore fibers a...

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confidence: 99%

Writing and Reading the Tubulin Code

Garnham

Roll-Mecak

2015

Journal of Biological Chemistry

179

180

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“…It has been demonstrated that axonal MTs are more resistant to the MT depolymerizing drug nocodazole compared to the dendritic MT population (Baas et al 1991;Witte et al 2008). Recently, a new posttranslational modification of tubulin has been identified that directly confers stability to MTs (Song et al 2013). Biochemical characterization of stable MT fractions demonstrated that polyamination of tubulin is directly involved in stabilizing neuronal MTs.…”

Section: Organization Of Axonal and Dendritic Microtubulesmentioning

confidence: 99%

Microtubule Organization and Microtubule-Associated Proteins (MAPs)

2016

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Dendrites have a unique microtubule organization. In vertebrates, dendritic microtubules are organized in antiparallel bundles, oriented with their plus ends either pointing away or toward the soma. The mixed microtubule arrays control intracellular trafficking and local signaling pathways, and are essential for dendrite development and function. The organization of microtubule arrays largely depends on the combined function of different microtubule regulatory factors or generally named microtubule-associated proteins (MAPs). Classical MAPs, also called structural MAPs, were identified more than 20 years ago based on their ability to bind to and copurify with microtubules. Most classical MAPs bind along the microtubule lattice and regulate microtubule polymerization, bundling, and stabilization. Recent evidences suggest that classical MAPs also guide motor protein transport, interact with the actin cytoskeleton, and act in various neuronal signaling networks. Here, we give an overview of microtubule organization in dendrites and the role of classical MAPs in dendrite development, dendritic spine formation, and synaptic plasticity. IntroductionMicrotubules (MTs) are cytoskeletal structures that play essential roles in all eukaryotic cells. MTs are important not only during cell division but also in non-dividing cells, where they are critical structures in numerous cellular processes such as cell motility, migration, differentiation, intracellular transport and organelle positioning. MTs are composed of two proteins, α-and β-tubulin, that form heterodimers and organize themselves in a head-to-tail manner. MTs are dynamic and they can rapidly switch between cycles of growth and shrinkage. This MT

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“…If there is no primary amine present, water may act as the attacking nucleophile, resulting in the deamidation of glutaminyl residues to glutamyl residues, ( Figure 1, example 3). Regarding the physiological roles played by the transglutaminase activity, recently transglutaminase-catalyzed polyamination of tubulin has been shown to stabilize axonal microtubules, suggesting an important role for these reactions also during some physiological processes, such as neurite outgrowth and axon maturation [4] . The reactions catalyzed by TGs occur with little change in free energy and hence should theoretically be reversible.…”

Section: Tgmentioning

confidence: 99%

Transglutaminase Activity as a Possible Molecular Mechanism in the Etiopathogenesis of Neurodegenerative Diseases

Gatta¹,

Cammarota²,

Iannaccone³

et al. 2016

Journal of Biochemistry and Molecular Biology Research

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characterized in part by aberrant cerebral transglutaminase activity and by increased cross-linked proteins in affected brains. This review focuses on the possible molecular mechanisms responsible for such diseases and on the possible therapeutic effects of transglutaminase inhibitors for patients with diseases characterized by aberrant transglutaminase activity. BIOCHEMISTRY OF THE TRANSGLUTAMINASESTransglutaminases (TGs, E.C. 2.3.2.13) are family of Ca 2+ -dependent enzymes which catalyze post-translational modifications of proteins. Examples of TG-catalyzed reactions include: (1) acyl transfer between the g-carboxamide group of a protein/polypeptide glutaminyl residue and the e-amino group of a protein/polypeptide lysyl residue; (2) attachment of a polyamine to the g-carboxamide of a glutaminyl residue; (3) deamidation of the g-carboxamide group of a protein/polypeptide glutaminyl residue (Figure 1) [1,2] . The reactions catalyzed by TGs occur by a two-step mechanism (ping-pong type), (Figure 2 ABSTRACTTransglutaminases are a family of Ca 2+ -dependent enzymes which catalyze post-translational modifications of proteins. The main activity of these enzymes is the cross-linking of glutaminyl residues of a protein/peptide substrate to lysyl residues of a protein/peptide co-substrate. In addition to lysyl residues, other second nucleophilic co-substrates may include monoamines or polyamines (to form mono-or bi-substituted/crosslinked adducts) or -OH groups (to form ester linkages). In absence of co-substrates, the nucleophile may be water, resulting in the net deamidation of the glutaminyl residue. Transglutaminase activity has been suggested to be involved in molecular mechanisms responsible for both physiological and pathological processes. In particular, transglutaminase activity has been shown to be

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Transglutaminase and Polyamination of Tubulin: Posttranslational Modification for Stabilizing Axonal Microtubules

Cited by 179 publications

References 53 publications

Writing and Reading the Tubulin Code

Writing and Reading the Tubulin Code

Microtubule Organization and Microtubule-Associated Proteins (MAPs)

Transglutaminase Activity as a Possible Molecular Mechanism in the Etiopathogenesis of Neurodegenerative Diseases

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