@article{f909ab67240f445680af4f7e88ac5b63,
title = "Structure of a Novel Dimeric SET Domain Methyltransferase that Regulates Cell Motility",
abstract = "Lysine methyltransferases (KMTs) were initially associated with transcriptional control through their methylation of histones and other nuclear proteins, but have since been found to regulate many other cellular activities. The apical complex lysine (K) methyltransferase (AKMT) of the human parasite Toxoplasma gondii was recently shown to play a critical role in regulating cellular motility. Here we report a 2.1-{\AA} resolution crystal structure of the conserved and functional C-terminal portion (aa289–709) of T. gondii AKMT. AKMT dimerizes via a unique intermolecular interface mediated by the C-terminal tetratricopeptide repeat-like domain together with a specific zinc-binding motif that is absent from all other KMTs. Disruption of AKMT dimerization impaired both its enzyme activity and parasite egress from infected host cells in vivo. Structural comparisons reveal that AKMT is related to the KMTs in the SMYD family, with, however, a number of distinct structural features in addition to the unusual dimerization interface. These features are conserved among the apicomplexan parasites and their free-living relatives, but not found in any known KMTs in animals. AKMT therefore is the founding member of a new subclass of KMT that has important implications for the evolution of the apicomplexans.",
keywords = "AKMT, egress, lysine methylation, parasite",
author = "Yulia Pivovarova and Jun Liu and Johannes Lesigang and Oliver Koldyka and Rene Rauschmeier and Ke Hu and Gang Dong",
note = "Funding Information: We are grateful to the staff at the beamlines of ID29 and BM29 at the European Synchrotron Radiation Facility for their help with X-ray diffraction and SAXS data collections. We also thank the staff at the MS facility of the MFPL for their assistance in our mass spectrometric measurements. We greatly appreciate Dr. Brooke Morriswood for critical reading of the manuscript and Dr. John M. Murray for carrying out a double-blind image analysis. This work was supported by grant P23440-B20 from the Austrian Science Fund (FWF) to G.D. and funding from the National Institutes of Health/National Institute of Allergy and Infectious Diseases (R01-AI098686) and the March of Dimes (6-FY15-198) awarded to K.H. Y.P. is enrolled in the Integrative Structural Biology PhD program funded by the FWF. Funding Information: We are grateful to the staff at the beamlines of ID29 and BM29 at the European Synchrotron Radiation Facility for their help with X-ray diffraction and SAXS data collections. We also thank the staff at the MS facility of the MFPL for their assistance in our mass spectrometric measurements. We greatly appreciate Dr. Brooke Morriswood for critical reading of the manuscript and Dr. John M. Murray for carrying out a double-blind image analysis. This work was supported by grant P23440-B20 from the Austrian Science Fund (FWF) to G.D. and funding from the National Institutes of Health/National Institute of Allergy and Infectious Diseases ( R01-AI098686 ) and the March of Dimes ( 6-FY15-198 ) awarded to K.H. Y.P. is enrolled in the Integrative Structural Biology PhD program funded by the FWF. Publisher Copyright: {\textcopyright} 2018 Elsevier Ltd",
year = "2018",
month = oct,
day = "19",
doi = "10.1016/j.jmb.2018.08.017",
language = "English (US)",
volume = "430",
pages = "4209--4229",
journal = "Journal of molecular biology",
issn = "0022-2836",
publisher = "Academic Press Inc.",
number = "21",
}