![]() The sensing of the tyrosine residue is essential for CLIP-170 and p150 glued for localization to growing microtubule tips, where they are involved in the regulation of microtubule dynamics and interactions of microtubules with subcellular structures ( Badin-Larçon et al., 2004 Peris et al., 2006 Bieling et al., 2008). For example, the microtubule plus end–tracking proteins (+TIPs) cytoplasmic linker protein-170 (CLIP-170) and large dynactin subunit p150 glued use their cytoskeleton-associated protein glycine-rich (CAP-Gly) domains to bind the C-terminal tyrosine of α-tubulin ( Steinmetz and Akhmanova, 2008). On a molecular level, tubulin tyrosination controls several key proteins. Together, these results underpin the vital role of TTL in physiological conditions and its implication in human pathologies. Furthermore, TTL suppression is linked to cell transformation and correlates with poor prognosis in patients suffering from diverse forms of cancers ( Lafanechère et al., 1998 Mialhe et al., 2001 Kato et al., 2004 Whipple et al., 2010). Remarkably, the enzyme is indispensable for cell and organism development TTL-null mice die right after birth due to disorganized neuronal networks ( Erck et al., 2005). TTL catalyzes the readdition of a tyrosine residue to the C terminus of detyrosinated α-tubulin as part of the evolutionary conserved tubulin tyrosination cycle ( Murofushi, 1980 Ersfeld et al., 1993 Westermann and Weber, 2003). One of the best-characterized representatives is tubulin tyrosine ligase (TTL), whose activity was discovered several decades ago ( Arce et al., 1975). Most of the enzymes involved in the generation and removal of post-translational modifications at the C-terminal tails of tubulin have recently been identified ( Ersfeld et al., 1993 Janke et al., 2005 Ikegami et al., 2006 van Dijk et al., 2007 Rogowski et al., 2009, 2010 Wloga et al., 2009 Kimura et al., 2010). Together, our data suggest that TTL has specifically evolved to recognize and modify tubulin, thus highlighting a fundamental role of the evolutionary conserved tubulin tyrosination cycle in regulating the microtubule cytoskeleton. It also reveals how TTL discriminates between α- and β-tubulin, and between different post-translationally modified forms of α-tubulin. The TTL–tubulin structure further illustrates how the enzyme binds the functionally crucial C-terminal tail sequence of α-tubulin and how this interaction catalyzes the tyrosination reaction. Biochemical and cellular assays revealed that specific tubulin dimer recognition controls the activity of the enzyme, and as a consequence, neuronal development. By solving crystal structures of TTL in complex with tubulin, we here demonstrate that TTL binds to the α and β subunits of tubulin and recognizes the curved conformation of the dimer. Despite the indispensable role of TTL in cell and organism development, its molecular mechanism of action is poorly understood. Tubulin tyrosine ligase (TTL) catalyzes the post-translational retyrosination of detyrosinated α-tubulin.
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