Structural basis for the target specificity of actin histidine methyltransferase SETD3

Dai, Shaobo; Horton, John R.; Woodcock, Clayton B.; Wilkinson, Alex W.; Zhang, Xing; Gozani, Or; Cheng, Xiaodong

doi:10.1038/s41467-019-11554-6

Structural basis for the target specificity of actin histidine methyltransferase SETD3

Journal Article · Tue Aug 06 00:00:00 EDT 2019 · Nature Communications

DOI:https://doi.org/10.1038/s41467-019-11554-6· OSTI ID:1571667

Dai, Shaobo ^[1]; ^[1]; Woodcock, Clayton B. ^[1]; Wilkinson, Alex W. ^[2]; Zhang, Xing ^[1]; ^[2]; ^[1]

Univ. of Texas MD Anderson Cancer Center, Houston, TX (United States)
Stanford Univ., CA (United States)

SETD3 is an actin histidine-N₃ methyltransferase, whereas other characterized SET-domain enzymes are protein lysine methyltransferases. We report that in a pre-reactive complex SETD3 binds the N₃-protonated form (N₃-H) of actin His73, and in a post-reactive product complex, SETD3 generates the methylated histidine in an N₁-protonated (N₁-H) and N₃-methylated form. During the reaction, the imidazole ring of His73 rotates ~105°, which shifts the proton from N₃ to N₁, thus ensuring that the target atom N₃ is deprotonated prior to the methyl transfer. Under the conditions optimized for lysine deprotonation, SETD3 has weak lysine methylation activity on an actin peptide in which the target His73 is substituted by a lysine. The structure of SETD3 with Lys73-containing peptide reveals a bent conformation of Lys73, with its side chain aliphatic carbons tracing along the edge of imidazole ring and the terminal ε-amino group occupying a position nearly identical to the N₃ atom of unmethylated histidine.

View Accepted Manuscript (DOE)

Research Organization:: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)

Sponsoring Organization:: National Institutes of Health (NIH); Cancer Prevention Research Institute of Texas (CPRIT)

OSTI ID:: 1571667

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 10; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

References (44)

Expression, Purification, and Characterization of Recombinant Ribulose-1,5-Bisphosphate Carboxylase/Oxygenase Large SubunitNϵ-Methyltransferase Zheng, Qi; Simel, Erica J.; Klein, Patricia E. Protein Expression and Purification, Vol. 14, Issue 1 https://doi.org/10.1006/prep.1998.0936	journal	October 1998
The SET8 H4K20 protein lysine methyltransferase has a long recognition sequence covering seven amino acid residues Kudithipudi, Srikanth; Dhayalan, Arunkumar; Kebede, Adam Fiseha Biochimie, Vol. 94, Issue 11 https://doi.org/10.1016/j.biochi.2012.04.024	journal	November 2012
Lysine methylation: Implications in neurodegenerative disease Rowe, Elyn M.; Xing, Viktoria; Biggar, Kyle K. Brain Research, Vol. 1707 https://doi.org/10.1016/j.brainres.2018.11.024	journal	March 2019
Specificity Analysis-Based Identification of New Methylation Targets of the SET7/9 Protein Lysine Methyltransferase Dhayalan, Arunkumar; Kudithipudi, Srikanth; Rathert, Philipp Chemistry & Biology, Vol. 18, Issue 1 https://doi.org/10.1016/j.chembiol.2010.11.014	journal	January 2011
SET for life: biochemical activities and biological functions of SET domain-containing proteins Herz, Hans-Martin; Garruss, Alexander; Shilatifard, Ali Trends in Biochemical Sciences, Vol. 38, Issue 12 https://doi.org/10.1016/j.tibs.2013.09.004	journal	December 2013
Structure and Catalytic Mechanism of a SET Domain Protein Methyltransferase Trievel, Raymond C.; Beach, Bridgette M.; Dirk, Lynnette M. A. Cell, Vol. 111, Issue 1 https://doi.org/10.1016/s0092-8674(02)01000-0	journal	October 2002
Many paths to methyltransfer: a chronicle of convergence Schubert, Heidi L.; Blumenthal, Robert M.; Cheng, Xiaodong Trends in Biochemical Sciences, Vol. 28, Issue 6 https://doi.org/10.1016/s0968-0004(03)00090-2	journal	June 2003
Cracking the Histone Code One, Two, Three Methyls, You're Out! Dutnall, Robert N. Molecular Cell, Vol. 12, Issue 1 https://doi.org/10.1016/s1097-2765(03)00282-x	journal	July 2003
Regulation of chromatin structure by site-specific histone H3 methyltransferases Rea, Stephen; Eisenhaber, Frank; O'Carroll, Dónal Nature, Vol. 406, Issue 6796 https://doi.org/10.1038/35020506	journal	August 2000
Lysine methylation of the NF-κB subunit RelA by SETD6 couples activity of the histone methyltransferase GLP at chromatin to tonic repression of NF-κB signaling Levy, Dan; Kuo, Alex J.; Chang, Yanqi Nature Immunology, Vol. 12, Issue 1 https://doi.org/10.1038/ni.1968	journal	December 2010
Mechanism of multiple lysine methylation by the SET domain enzyme Rubisco LSMT Trievel, Raymond C.; Flynn, E. Megan; Houtz, Robert L. Nature Structural & Molecular Biology, Vol. 10, Issue 7 https://doi.org/10.1038/nsb946	journal	June 2003
Lysine methylation of transcription factors in cancer Han, Dong; Huang, Mengxi; Wang, Ting Cell Death & Disease, Vol. 10, Issue 4 https://doi.org/10.1038/s41419-019-1524-2	journal	March 2019
SETD3 is an actin histidine methyltransferase that prevents primary dystocia Wilkinson, Alex W.; Diep, Jonathan; Dai, Shaobo Nature, Vol. 565, Issue 7739 https://doi.org/10.1038/s41586-018-0821-8	journal	December 2018
Structural origins for the product specificity of SET domain protein methyltransferases Couture, J. -F.; Dirk, L. M. A.; Brunzelle, J. S. Proceedings of the National Academy of Sciences, Vol. 105, Issue 52 https://doi.org/10.1073/pnas.0806712105	journal	December 2008
Rubisco in complex with Rubisco large subunit methyltransferase Raunser, S.; Magnani, R.; Huang, Z. Proceedings of the National Academy of Sciences, Vol. 106, Issue 9 https://doi.org/10.1073/pnas.0810563106	journal	February 2009
In Vitro and in Vivo Analyses of a Phe/Tyr Switch Controlling Product Specificity of Histone Lysine Methyltransferases Collins, Robert E.; Tachibana, Makoto; Tamaru, Hisashi Journal of Biological Chemistry, Vol. 280, Issue 7 https://doi.org/10.1074/jbc.m410483200	journal	December 2004
Structural basis of SETD6-mediated regulation of the NF-kB network via methyl-lysine signaling Chang, Yanqi; Levy, Dan; Horton, John R. Nucleic Acids Research, Vol. 39, Issue 15 https://doi.org/10.1093/nar/gkr256	journal	April 2011
Phaser crystallographic software McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D. Journal of Applied Crystallography, Vol. 40, Issue 4 https://doi.org/10.1107/s0021889807021206	journal	July 2007
Multiparametric scaling of diffraction intensities Otwinowski, Zbyszek; Borek, Dominika; Majewski, Wladyslaw Acta Crystallographica Section A Foundations of Crystallography, Vol. 59, Issue 3 https://doi.org/10.1107/s0108767303005488	journal	April 2003
Coot model-building tools for molecular graphics Emsley, Paul; Cowtan, Kevin Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132 https://doi.org/10.1107/s0907444904019158	journal	November 2004
Towards automated crystallographic structure refinement with phenix.refine Afonine, Pavel V.; Grosse-Kunstleve, Ralf W.; Echols, Nathaniel Acta Crystallographica Section D Biological Crystallography, Vol. 68, Issue 4 https://doi.org/10.1107/s0907444912001308	journal	March 2012
Beyond histones - the expanding roles of protein lysine methylation Wu, Zhouran; Connolly, Justin; Biggar, Kyle K. The FEBS Journal, Vol. 284, Issue 17 https://doi.org/10.1111/febs.14056	journal	May 2017
The epigenetic magic of histone lysine methylation.: Delivered on 6 July 2005 at the 30th FEBS Congress in Budapest, Hungary Jenuwein, Thomas FEBS Journal, Vol. 273, Issue 14 https://doi.org/10.1111/j.1742-4658.2006.05343.x	journal	July 2006
Electron diffraction and the hydrogen atom McCusker, Lynne B. Science, Vol. 355, Issue 6321 https://doi.org/10.1126/science.aal4570	journal	January 2017
Methyltransferase-Glo: a universal, bioluminescent and homogenous assay for monitoring all classes of methyltransferases Hsiao, Kevin; Zegzouti, Hicham; Goueli, Said A. Epigenomics, Vol. 8, Issue 3 https://doi.org/10.2217/epi.15.113	journal	March 2016
SETD3 protein is the actin-specific histidine N-methyltransferase Kwiatkowski, Sebastian; Seliga, Agnieszka K.; Vertommen, Didier eLife, Vol. 7 https://doi.org/10.7554/elife.37921	journal	December 2018
Cloning and developmental expression of pea ribulose-1,5-bisphosphate carboxylase/oxygenase large subunit N-methyltransferase Klein, Robert R.; Houtz, Robert L. Plant Molecular Biology, Vol. 27, Issue 2 https://doi.org/10.1007/BF00020181	journal	January 1995
Structure of the Neurospora SET Domain Protein DIM-5, a Histone H3 Lysine Methyltransferase Zhang, Xing; Tamaru, Hisashi; Khan, Seema I. Cell, Vol. 111, Issue 1 https://doi.org/10.1016/S0092-8674(02)00999-6	journal	October 2002
Structure and Catalytic Mechanism of a SET Domain Protein Methyltransferase Trievel, Raymond C.; Beach, Bridgette M.; Dirk, Lynnette M. A. Cell, Vol. 111, Issue 1 https://doi.org/10.1016/S0092-8674(02)01000-0	journal	October 2002
Many paths to methyltransfer: a chronicle of convergence Schubert, Heidi L.; Blumenthal, Robert M.; Cheng, Xiaodong Trends in Biochemical Sciences, Vol. 28, Issue 6 https://doi.org/10.1016/S0968-0004(03)00090-2	journal	June 2003
Structural Basis for the Product Specificity of Histone Lysine Methyltransferases Zhang, Xing; Yang, Zhe; Khan, Seema I. Molecular Cell, Vol. 12, Issue 1 https://doi.org/10.1016/S1097-2765(03)00224-7	journal	July 2003
Analysis of the Substrate Specificity of the Dim-5 Histone Lysine Methyltransferase Using Peptide Arrays Rathert, Philipp; Zhang, Xing; Freund, Christian Chemistry & Biology, Vol. 15, Issue 1 https://doi.org/10.1016/j.chembiol.2007.11.013	journal	January 2008
Protein lysine methyltransferase G9a acts on non-histone targets Rathert, Philipp; Dhayalan, Arunkumar; Murakami, Marie Nature Chemical Biology, Vol. 4, Issue 6 https://doi.org/10.1038/nchembio.88	journal	April 2008
The molecular hallmarks of epigenetic control Allis, C. David; Jenuwein, Thomas Nature Reviews Genetics, Vol. 17, Issue 8 https://doi.org/10.1038/nrg.2016.59	journal	June 2016
In Vitro and in Vivo Analyses of a Phe/Tyr Switch Controlling Product Specificity of Histone Lysine Methyltransferases Collins, Robert E.; Tachibana, Makoto; Tamaru, Hisashi Journal of Biological Chemistry, Vol. 280, Issue 7 https://doi.org/10.1074/jbc.M410483200	journal	December 2004
Nonhistone Lysine Methylation in the Regulation of Cancer Pathways Carlson, Scott M.; Gozani, Or Cold Spring Harbor Perspectives in Medicine, Vol. 6, Issue 11 https://doi.org/10.1101/cshperspect.a026435	journal	August 2016
Phaser crystallographic software McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D. Journal of Applied Crystallography, Vol. 40, Issue 4 https://doi.org/10.1107/S0021889807021206	journal	July 2007
Multiparametric scaling of diffraction intensities Otwinowski, Zbyszek; Borek, Dominika; Majewski, Wladyslaw Acta Crystallographica Section A Foundations of Crystallography, Vol. 59, Issue 3 https://doi.org/10.1107/S0108767303005488	journal	April 2003
Coot model-building tools for molecular graphics Emsley, Paul; Cowtan, Kevin Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132 https://doi.org/10.1107/S0907444904019158	journal	November 2004
Towards automated crystallographic structure refinement with phenix.refine Afonine, Pavel V.; Grosse-Kunstleve, Ralf W.; Echols, Nathaniel Acta Crystallographica Section D Biological Crystallography, Vol. 68, Issue 4 https://doi.org/10.1107/S0907444912001308	journal	March 2012
Histone Lysine Methylation and Neurodevelopmental Disorders Kim, Jeong-Hoon; Lee, Jang; Lee, Im-Soon International Journal of Molecular Sciences, Vol. 18, Issue 7 https://doi.org/10.3390/ijms18071404	journal	June 2017
Specificity Analysis of Protein Lysine Methyltransferases Using SPOT Peptide Arrays Kudithipudi, Srikanth; Kusevic, Denis; Weirich, Sara Journal of Visualized Experiments, Issue 93 https://doi.org/10.3791/52203	journal	January 2014
SETD3 protein is the actin-specific histidine N-methyltransferase Kwiatkowski, Sebastian; Seliga, Agnieszka K.; Vertommen, Didier eLife, Vol. 7 https://doi.org/10.7554/eLife.37921	journal	December 2018
Structural insights into SETD3-mediated histidine methylation on β-actin Guo, Qiong; Liao, Shanhui; Kwiatkowski, Sebastian eLife, Vol. 8 https://doi.org/10.7554/eLife.43676	journal	February 2019

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