Journal
JOURNAL OF MOLECULAR BIOLOGY
Volume 426, Issue 14, Pages 2605-2616Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2014.05.009
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Funding
- National Institutes of Health Research Service Award [5 T32 GM07616]
- Albert Wyrick V Scholar Award of the V Foundation for Cancer Research
- 54th Mallinckrodt Scholar Award of the Edward Mallinckrodt
- Kimmel Scholar Award of the Sidney Kimmel Foundation for Cancer Research
- Howard Hughes Medical Institute
- Gordon and Betty Moore Foundation
- Department of Energy
- National Institutes of Health
- Jr. Foundation
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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 a-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 A 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 that is critical for enzymatic activity is identified, suggesting that specificity is achieved by interactions with the a-tubulin substrate that extend outside of the modified surface loop. An analysis of MEC-17 mutants in Caenorhabditis elegans shows that enzymatic activity is dispensable for touch sensitivity. (C) 2014 Elsevier Ltd. All rights reserved.
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