Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 109, Issue 48, Pages 19649-19654Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1209343109
Keywords
cilium; crystal structure; post-translational modification
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Funding
- Emmy Noether Grant Deutsche Forschungsgemeinschaft [LO1627/1-1]
- European Research Council [310343]
- European Molecular Biology Organization Young Investigator program
- Austrian Science Fund [J3148-B12]
- European Research Council (ERC) [310343] Funding Source: European Research Council (ERC)
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Acetylation of lysine residues is an important posttranslational modification found in all domains of life. alpha-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 alpha-tubulin acetyltransferases. Here, we present the structure of the human alpha-tubulin acetyltransferase catalytic domain bound to its cosubstrate acetyl-CoA at 1.05 angstrom resolution. Compared with other lysine acetyltransferases of known structure, alpha-tubulin acetyltransferase displays a relatively well-conserved cosubstrate binding pocket but is unique in its active site and putative alpha-tubulin binding site. Using acetylation assays with structure-guided mutants, we map residues important for acetylCoA 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 alpha-tubulin acetyltransferases uses a reaction mechanism different from other lysine acetyltransferases characterized to date.
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