TTLLs polyglutamylate tubulin

Stable Identifier
Reaction [transition]
Homo sapiens
Locations in the PathwayBrowser
SVG |   | PPTX  | SBGN
Click the image above or here to open this reaction in the Pathway Browser
The layout of this reaction may differ from that in the pathway view due to the constraints in pathway layout

Tubulin is modified by glutamylation and glycylation, the additon of peptide branches made of glutamyl or glycyl residues respectively, which are attached to the gamma-carboxyl group of glutamic acids within the C-terminal tail domains of alpha- and beta-tubulin. Glutamylation, the most prevalent tubulin posttranslational modification, marks stable microtubules and regulates recruitment and activity of microtubule-interacting proteins. Hyperglutamylation in Purkinje cell degeneration (pcd) mice leads to neurodegeneration (Rogowski et al. 2010).

Nine enzymes of the tubulin tyrosine ligase-like (TTLL) family catalyze glutamylation (Garhnam & Roll-Mecak 2012, Garnham et al. 2015). TTLLs can have a preference for either alpha- or beta-tubulin, although many are able to modify either (Janke et al. 2005, Ikegami et al. 2006, van Dijk et al. 2007). Initial characterization of the mouse TTLL family showed that TTLL1, 5, 6, 11, and 13 preferentially poly-glutamylate alpha-tubulin, while TTLL4 and 7 prefer beta-tubulin. While TTLL1 has a preference for alpha-tubulin (Janke et al. 2005), TTLL1 knockout mice displayed decreased glutamylation on alpha- and beta-tubulin (Ikegami et al. 2010). The molecular determinants for specificity are poorly understood and specificity can differ between organisms, preventing an unambiguous classification of TTLLs by their alpha/beta preference. TTLL4, 5, and 7 have been described as initiases, adding a branched glutamic acid to the tubulin tail, while TTLL6, 11, and 13 were suggested to be elongases, adding poly-Glu chains of variable lengths to the branched glutamic acid (Garhnam & Roll-Mecak 2012). The specificity of mammalian TTLL2, 9, and TTLL12 are unknown.

TTLL3, 8, and 10 are glycylases that glycate rather than glutamylate tubulin (Ikegami et al. 2008, Ikegami & Setou 2009, Rogowski et al. 2009, Wloga et al. 2009), with TTLL3 and 8 serving as initiases, and TTLL10 serving as an elongase.

TTLL7, the most abundant glutamylase in neurons, modifies both alpha- and beta-tubulin tail peptides in isolation but shows a preference for beta-tubulin when presented with microtubules. TTLL7 catalyzes the initiatial glutamylation of Beta-tubulin glutamates at multiple internal positions in the Beta-tail, and also the addition of subsequent glutamates to existing branched glutamates (Mukai et al. 2009).

Literature References
PubMed ID Title Journal Year
16901895 TTLL7 is a mammalian beta-tubulin polyglutamylase required for growth of MAP2-positive neurites

Mukai, M, Setou, M, Tsuchida, J, Macgregor, GR, Heier, RL, Ikegami, K

J. Biol. Chem. 2006
17499049 A targeted multienzyme mechanism for selective microtubule polyglutamylation

Lacroix, B, Eddé, B, Rogowski, K, Janke, C, Miro, J, van Dijk, J

Mol. Cell 2007
15890843 Tubulin polyglutamylase enzymes are members of the TTL domain protein family

Gaertig, J, Eddé, B, Strub, JM, Boucher, D, Temurak, N, Suryavanshi, S, Rogowski, K, van Dijk, J, Regnard, C, Wloga, D, Kajava, AV, van Dorsselaer, A, Janke, C

Science 2005
Event Information
Go Biological Process
Catalyst Activity

tubulin-glutamic acid ligase activity of TTLLs [cytosol]

Orthologous Events
Cite Us!