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Published July 15, 2014 | Supplemental Material
Journal Article Open

Structural and Functional Characterization of the α-Tubulin Acetyltransferase MEC-17


Tubulin protomers undergo an extensive array of post-translational modifications to tailor microtubules to specific tasks. One such modification, the acetylation of lysine-40 of α-tubulin, located in the lumen of microtubules, is associated with stable, long-living microtubule structures. MEC-17 was recently identified as the acetyltransferase that mediates this event. We have determined the crystal structure of the catalytic core of human MEC-17 in complex with its cofactor acetyl-CoA at 1.7 Å resolution. The structure reveals that the MEC-17 core adopts a canonical Gcn5-related N-acetyltransferase (GNAT) fold that is decorated with extensive surface loops. An enzymatic analysis of 33 MEC-17 surface mutants identifies hot-spot residues for catalysis and substrate recognition. A large, evolutionarily conserved hydrophobic surface patch is identified that is critical for enzymatic activity, suggesting that specificity is achieved by interactions with the α-tubulin substrate that extend outside of the modified surface loop. An analysis of MEC-17 mutants in C. elegans shows that enzymatic activity is dispensable for touch sensitivity.

Additional Information

© 2014 Published by Elsevier Ltd. Received date: 28 March 2014. Revised date: 5 May 2014. Accepted date: 6 May 2014. We thank Daniel H. Lin, Alina Patke, Tobias Stuwe, Karsten Thierbach, and Yunji Wu for critical reading of the manuscript, David King for mass spectrometry analysis, Maxene Nachury and Irini Topalidou for providing material, Jens Kaiser and the scientific staff of SSRL beamline 12-2 for their support with X-ray diffraction measurements. We acknowledge the Gordon and Betty Moore Foundation for their support of the Molecular Observatory at the California Institute of Technology. The operations at the SSRL are supported by the Department of Energy and by the National Institutes of Health. AMD and PJM are supported by a National Institutes of Health Research Service Award (5 T32 GM07616). AH was supported by the Albert Wyrick V Scholar Award of the V Foundation for Cancer Research, the 54th Mallinckrodt Scholar Award of the Edward Mallinckrodt, Jr. Foundation, and a Kimmel Scholar Award of the Sidney Kimmel Foundation for Cancer Research. Research supported in part by the Howard Hughes Medical Institute, with which P.W.S. is an investigator.

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