Carboxyterminal post-translational modifications of tubulin (Homo sapiens)
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Description
Tubulins fold into compact globular domains with less structured carboxyterminal tails. These tails vary in sequence between tubulin isoforms and are exposed on the surfaces of microtubules. They can undergo a variety of posttranslational modifications, including the attachment and removal of polyglutamate chains and in the case of alpha-tunulins the loss and reattachment of a terminal tyrosine (Tyr) residue. These modifications are associated with changes in the rigidity and stability of microtubules (Song & Brady 2015; Yu et al. 2015).
Mutations affecting these modification processes can have severe effects on phenotype (e.g., Ikegami et al. 2007). Nevertheless, the precise molecular mechanisms by which these changes in tubulin structure modulate its functions remain unclear, so these modification processes are simply annotated here as a series of chemical transformations of tubulins. View original pathway at:Reactome.
Mutations affecting these modification processes can have severe effects on phenotype (e.g., Ikegami et al. 2007). Nevertheless, the precise molecular mechanisms by which these changes in tubulin structure modulate its functions remain unclear, so these modification processes are simply annotated here as a series of chemical transformations of tubulins. View original pathway at:Reactome.
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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).
A complex containing TTLL1 performs alpha-tubulin polyglutamylation in the brain (Ikegami et al. 2007). In this event polyglutamylation is arbitrarily shown on only one tubulin protofilament within the microtubule.