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Atomic resolution structure of human α-tubulin acetyltransferase bound to acetyl-CoA

Taschner, Michael, Vetter, Melanie, Lorentzen, Esben
Proceedings of the National Academy of Sciences of the United States of America 2012 v.109 no.48 pp. 19649-19654
acetyl coenzyme A, acetylation, acetyltransferases, active sites, axons, binding sites, catalytic activity, cilia, glutamine, histones, humans, lysine, microtubules, mutants, post-translational modification, tubulin
Acetylation of lysine residues is an important posttranslational modification found in all domains of life. α-tubulin is specifically acetylated on lysine 40, a modification that serves to stabilize microtubules of axons and cilia. Whereas histone acetyltransferases have been extensively studied, there is no structural and mechanistic information available on α-tubulin acetyltransferases. Here, we present the structure of the human α-tubulin acetyltransferase catalytic domain bound to its cosubstrate acetyl-CoA at 1.05 Å resolution. Compared with other lysine acetyltransferases of known structure, α-tubulin acetyltransferase displays a relatively well-conserved cosubstrate binding pocket but is unique in its active site and putative α-tubulin binding site. Using acetylation assays with structure-guided mutants, we map residues important for acetyl-CoA binding, substrate binding, and catalysis. This analysis reveals a basic patch implicated in substrate binding and a conserved glutamine residue required for catalysis, demonstrating that the family of α-tubulin acetyltransferases uses a reaction mechanism different from other lysine acetyltransferases characterized to date.