NMT1 and NMT2 are lysine myristoyltransferases regulating the ARF6 GTPase cycle

Kosciuk, Tatsiana; Price, Ian R.; Zhang, Xiaoyu; Zhu, Chengliang; Johnson, Kayla N.; Zhang, Shuai; Halaby, Steve L.; Komaniecki, Garrison P.; Yang, Min; DeHart, Caroline J.; Thomas, Paul M.; Kelleher, Neil L.; Fromme, J. Christopher; Lin, Hening

doi:10.1038/s41467-020-14893-x

Title: NMT1 and NMT2 are lysine myristoyltransferases regulating the ARF6 GTPase cycle

Journal Article · Wed Feb 26 00:00:00 EST 2020 · Nature Communications

DOI:https://doi.org/10.1038/s41467-020-14893-x· OSTI ID:1619536

;

; Zhang, Xiaoyu; Zhu, Chengliang; Johnson, Kayla N.; Zhang, Shuai; Halaby, Steve L.; Komaniecki, Garrison P.; Yang, Min; DeHart, Caroline J.;

;

Abstract Lysine fatty acylation in mammalian cells was discovered nearly three decades ago, yet the enzymes catalyzing it remain unknown. Unexpectedly, we find that human N-terminal glycine myristoyltransferases (NMT) 1 and 2 can efficiently myristoylate specific lysine residues. They modify ADP-ribosylation factor 6 (ARF6) on lysine 3 allowing it to remain on membranes during the GTPase cycle. We demonstrate that the NAD ⁺ -dependent deacylase SIRT2 removes the myristoyl group, and our evidence suggests that NMT prefers the GTP-bound while SIRT2 prefers the GDP-bound ARF6. This allows the lysine myrisotylation-demyristoylation cycle to couple to and promote the GTPase cycle of ARF6. Our study provides an explanation for the puzzling dissimilarity of ARF6 to other ARFs and suggests the existence of other substrates regulated by this previously unknown function of NMT. Furthermore, we identified a NMT/SIRT2-ARF6 regulatory axis, which may offer new ways to treat human diseases.

View Journal Article

Cite

Export

Save

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS); Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). Advanced Light Source (ALS)

Sponsoring Organization:: National Institutes of Health (NIH); National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK); National Institute of General Medical Sciences (NIGMS); Howard Hughes Medical Institute (HHMI); National Science Foundation (NSF); USDOE Office of Science (SC)

Grant/Contract Number:: AC02-06CH11357; AC02-05CH11231; NIH P41 GM108569; NIH S10RR025502; NYSTEM C029155; S10OD021527; P30 GM124169; DMR-1829070; GM-124166; DGE-1650441

OSTI ID:: 1619536

Alternate ID(s):: OSTI ID: 1606437

Journal Information:: Nature Communications, Journal Name: Nature Communications Vol. 11 Journal Issue: 1; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United Kingdom

Language:: English

Citation Metrics:

Cited by: 35 works

Citation information provided by
Web of Science

References (52)

The Myristoylated Amino Terminus of ADP-ribosylation Factor 1 Is a Phospholipid- and GTP-sensitive Switch Randazzo, Paul A.; Terui, Takeshi; Sturch, Stacey Journal of Biological Chemistry, Vol. 270, Issue 24 https://doi.org/10.1074/jbc.270.24.14809	journal	June 1995
Nε-fatty acylation of multiple membrane-associated proteins by Shigella IcsB effector to modulate host function Liu, Wang; Zhou, Yan; Peng, Tao Nature Microbiology, Vol. 3, Issue 9 https://doi.org/10.1038/s41564-018-0215-6	journal	July 2018
Endocytosed Transferrin Receptors Recycle via Distinct Dynamin and Phosphatidylinositol 3-Kinase-dependent Pathways van Dam, Ellen M.; ten Broeke, Toine; Jansen, Karen Journal of Biological Chemistry, Vol. 277, Issue 50 https://doi.org/10.1074/jbc.M206271200	journal	October 2002
Identifying the functional contribution of the defatty-acylase activity of SIRT6 Zhang, Xiaoyu; Khan, Saba; Jiang, Hong Nature Chemical Biology, Vol. 12, Issue 8 https://doi.org/10.1038/nchembio.2106	journal	June 2016
SIRT6 regulates TNF-α secretion through hydrolysis of long-chain fatty acyl lysine Jiang, Hong; Khan, Saba; Wang, Yi Nature, Vol. 496, Issue 7443 https://doi.org/10.1038/nature12038	journal	April 2013
Validation of N-myristoyltransferase as an antimalarial drug target using an integrated chemical biology approach Wright, Megan H.; Clough, Barbara; Rackham, Mark D. Nature Chemistry, Vol. 6, Issue 2 https://doi.org/10.1038/nchem.1830	journal	December 2013
Expression of N-Myristoyltransferase Inhibitor Protein and Its Relationship to c-Src Levels in Human Colon Cancer Cell Lines Rajala, Raju V. S.; Dehm, Scott; Bi, Xuguang Biochemical and Biophysical Research Communications, Vol. 273, Issue 3 https://doi.org/10.1006/bbrc.2000.3066	journal	July 2000
Sirt5 Is a NAD-Dependent Protein Lysine Demalonylase and Desuccinylase Du, J.; Zhou, Y.; Su, X. Science, Vol. 334, Issue 6057 https://doi.org/10.1126/science.1207861	journal	November 2011
A SIRT2-Selective Inhibitor Promotes c-Myc Oncoprotein Degradation and Exhibits Broad Anticancer Activity Jing, Hui; Hu, Jing; He, Bin Cancer Cell, Vol. 29, Issue 3 https://doi.org/10.1016/j.ccell.2016.02.007	journal	March 2016
A regulatory role for ARF6 in receptor-mediated endocytosis D'Souza-Schorey, C.; Li, G.; Colombo, M. Science, Vol. 267, Issue 5201 https://doi.org/10.1126/science.7855600	journal	February 1995
SIRT2 and lysine fatty acylation regulate the transforming activity of K-Ras4a Jing, Hui; Zhang, Xiaoyu; Wisner, Stephanie A. eLife, Vol. 6 https://doi.org/10.7554/eLife.32436	journal	December 2017
The Arf6 GEF GEP100/BRAG2 Regulates Cell Adhesion by Controlling Endocytosis of β1 Integrins Dunphy, Jillian L.; Moravec, Radim; Ly, Kim Current Biology, Vol. 16, Issue 3 https://doi.org/10.1016/j.cub.2005.12.032	journal	February 2006
Robust Fluorescent Detection of Protein Fatty-Acylation with Chemical Reporters Charron, Guillaume; Zhang, Mingzi M.; Yount, Jacob S. Journal of the American Chemical Society, Vol. 131, Issue 13 https://doi.org/10.1021/ja810122f	journal	April 2009
A Glycoconjugated SIRT2 Inhibitor with Aqueous Solubility Allows Structure-Based Design of SIRT2 Inhibitors Hong, Jun Young; Price, Ian Robert; Bai, Jessica Jingyi ACS Chemical Biology, Vol. 14, Issue 8 https://doi.org/10.1021/acschembio.9b00384	journal	June 2019
The Structural Basis of Ordered Substrate Binding by Serotonin N-Acetyltransferase Hickman, Alison Burgess; Namboodiri, M. A. A.; Klein, David C. Cell, Vol. 97, Issue 3 https://doi.org/10.1016/S0092-8674(00)80745-X	journal	April 1999
Pathways and mechanisms of endocytic recycling Grant, Barth D.; Donaldson, Julie G. Nature Reviews Molecular Cell Biology, Vol. 10, Issue 9 https://doi.org/10.1038/nrm2755	journal	September 2009
The structural GDP/GTP cycle of human Arf6 Pasqualato, Sebastiano; Ménétrey, Julie; Franco, Michel EMBO reports, Vol. 2, Issue 3 https://doi.org/10.1093/embo-reports/kve043	journal	March 2001
Lipid Modifications of Trimeric G Proteins Wedegaertner, Philip B.; Wilson, Paul T.; Bourne, Henry R. Journal of Biological Chemistry, Vol. 270, Issue 2 https://doi.org/10.1074/jbc.270.2.503	journal	January 1995
The intracellular trafficking pathway of transferrin Mayle, Kristine M.; Le, Alexander M.; Kamei, Daniel T. Biochimica et Biophysica Acta (BBA) - General Subjects, Vol. 1820, Issue 3 https://doi.org/10.1016/j.bbagen.2011.09.009	journal	March 2012
SIRT7 Is an RNA-Activated Protein Lysine Deacylase Tong, Zhen; Wang, Miao; Wang, Yi ACS Chemical Biology, Vol. 12, Issue 1 https://doi.org/10.1021/acschembio.6b00954	journal	December 2016
Fragment-derived inhibitors of human N-myristoyltransferase block capsid assembly and replication of the common cold virus Mousnier, Aurélie; Bell, Andrew S.; Swieboda, Dawid P. Nature Chemistry, Vol. 10, Issue 6 https://doi.org/10.1038/s41557-018-0039-2	journal	May 2018
ARF6 Targets Recycling Vesicles to the Plasma Membrane: Insights from an Ultrastructural Investigation D'Souza-Schorey, Crislyn; van Donselaar, Elly; Hsu, Victor W. The Journal of Cell Biology, Vol. 140, Issue 3 https://doi.org/10.1083/jcb.140.3.603	journal	February 1998
The Small G Proteins of the Arf Family and Their Regulators Gillingham, Alison K.; Munro, Sean Annual Review of Cell and Developmental Biology, Vol. 23, Issue 1 https://doi.org/10.1146/annurev.cellbio.23.090506.123209	journal	November 2007
The Small GTPase Arf6: An Overview of Its Mechanisms of Action and of Its Role in Host–Pathogen Interactions and Innate Immunity Van Acker, Tim; Tavernier, Jan; Peelman, Frank International Journal of Molecular Sciences, Vol. 20, Issue 9 https://doi.org/10.3390/ijms20092209	journal	May 2019
SIRT6 regulates Ras-related protein R-Ras2 by lysine defatty-acylation Zhang, Xiaoyu; Spiegelman, Nicole A.; Nelson, Ornella D. eLife, Vol. 6 https://doi.org/10.7554/eLife.25158	journal	April 2017
N ^ε -Fatty acylation of Rho GTPases by a MARTX toxin effector Zhou, Yan; Huang, Chunfeng; Yin, Li Science, Vol. 358, Issue 6362 https://doi.org/10.1126/science.aam8659	journal	October 2017
GGA3 Functions as a Switch to Promote Met Receptor Recycling, Essential for Sustained ERK and Cell Migration Parachoniak, Christine Anna; Luo, Yi; Abella, Jasmine Vanessa Developmental Cell, Vol. 20, Issue 6 https://doi.org/10.1016/j.devcel.2011.05.007	journal	June 2011
Crystal structure of the anti-fungal target N-myristoyl transferase Weston, Simon A.; Camble, Roger; Colls, Jeremy Nature Structural Biology, Vol. 5, Issue 3 https://doi.org/10.1038/nsb0398-213	journal	March 1998
N-terminal protein modifications: Bringing back into play the ribosome Giglione, Carmela; Fieulaine, Sonia; Meinnel, Thierry Biochimie, Vol. 114 https://doi.org/10.1016/j.biochi.2014.11.008	journal	July 2015
Development of Small-Molecule Trypanosoma brucei N -Myristoyltransferase Inhibitors: Discovery and Optimisation of a Novel Binding Mode Spinks, Daniel; Smith, Victoria; Thompson, Stephen ChemMedChem, Vol. 10, Issue 11 https://doi.org/10.1002/cmdc.201500301	journal	September 2015
Protein Lipidation: Occurrence, Mechanisms, Biological Functions, and Enabling Technologies Jiang, Hong; Zhang, Xiaoyu; Chen, Xiao Chemical Reviews, Vol. 118, Issue 3 https://doi.org/10.1021/acs.chemrev.6b00750	journal	December 2017
Palmitoylation of multiple Src-family kinases at a homologous N-terminal motif Koegl, M.; Zlatkine, P.; Ley, S. C. Biochemical Journal, Vol. 303, Issue 3 https://doi.org/10.1042/bj3030749	journal	November 1994
Global profiling of co- and post-translationally N-myristoylated proteomes in human cells Thinon, Emmanuelle; Serwa, Remigiusz A.; Broncel, Malgorzata Nature Communications, Vol. 5, Issue 1 https://doi.org/10.1038/ncomms5919	journal	September 2014
Validation of N-myristoyltransferase as Potential Chemotherapeutic Target in Mammal-Dwelling Stages of Trypanosoma cruzi Herrera, Linda J.; Brand, Stephen; Santos, Andres PLOS Neglected Tropical Diseases, Vol. 10, Issue 4 https://doi.org/10.1371/journal.pntd.0004540	journal	April 2016
Cytohesin 2/ARF6 regulates preadipocyte migration through the activation of ERK1/2 Davies, Jonathon C. B.; Tamaddon-Jahromi, Salman; Jannoo, Riaz Biochemical Pharmacology, Vol. 92, Issue 4 https://doi.org/10.1016/j.bcp.2014.09.023	journal	December 2014
Overexpression of wild-type and mutant ARF1 and ARF6: distinct perturbations of nonoverlapping membrane compartments. Peters, P. J.; Hsu, V. W.; Ooi, C. E. The Journal of Cell Biology, Vol. 128, Issue 6 https://doi.org/10.1083/jcb.128.6.1003	journal	March 1995
Features and development of Coot Emsley, P.; Lohkamp, B.; Scott, W. G. Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4 https://doi.org/10.1107/S0907444910007493	journal	March 2010
ARF6-dependent activation of ERK and Rac1 modulates epithelial tubule development Tushir, Jogender Singh; D'Souza-Schorey, Crislyn The EMBO Journal, Vol. 26, Issue 7 https://doi.org/10.1038/sj.emboj.7601644	journal	March 2007
N-myristoyltransferase: A potential novel diagnostic marker for colon cancer Shrivastav, Anuraag; Varma, Shailly; Saxena, Anurag Journal of Translational Medicine, Vol. 5, Issue 1 https://doi.org/10.1186/1479-5876-5-58	journal	January 2007
Structural Biology of Arf and Rab GTPases’ Effector Recruitment and Specificity Khan, Amir R.; Ménétrey, Julie Structure, Vol. 21, Issue 8 https://doi.org/10.1016/j.str.2013.06.016	journal	August 2013
PHENIX: a comprehensive Python-based system for macromolecular structure solution Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221 https://doi.org/10.1107/S0907444909052925	journal	January 2010
ARF6-Regulated Shedding of Tumor Cell-Derived Plasma Membrane Microvesicles Muralidharan-Chari, Vandhana; Clancy, James; Plou, Carolyn Current Biology, Vol. 19, Issue 22 https://doi.org/10.1016/j.cub.2009.09.059	journal	December 2009
The GDP-bound form of Arf6 is located at the plasma membrane Macia, E. Journal of Cell Science, Vol. 117, Issue 11 https://doi.org/10.1242/jcs.01090	journal	May 2004
Myristyl acylation of the tumor necrosis factor alpha precursor on specific lysine residues. Stevenson, F. T.; Bursten, S. L.; Locksley, R. M. The Journal of Experimental Medicine, Vol. 176, Issue 4 https://doi.org/10.1084/jem.176.4.1053	journal	October 1992
N -Myristoyltransferase Inhibition Induces ER-Stress, Cell Cycle Arrest, and Apoptosis in Cancer Cells Thinon, Emmanuelle; Morales-Sanfrutos, Julia; Mann, David J. ACS Chemical Biology, Vol. 11, Issue 8 https://doi.org/10.1021/acschembio.6b00371	journal	June 2016
Structures of Saccharomyces cerevisiae N -myristoyltransferase with Bound MyristoylCoA and Peptide Provide Insights about Substrate Recognition and Catalysis ^† Farazi, Thalia A.; Waksman, Gabriel; Gordon, Jeffrey I. Biochemistry, Vol. 40, Issue 21 https://doi.org/10.1021/bi0101401	journal	May 2001
ADP ribosylation factor 6 (ARF6) controls amyloid precursor protein (APP) processing by mediating the endosomal sorting of BACE1 Sannerud, R.; Declerck, I.; Peric, A. Proceedings of the National Academy of Sciences, Vol. 108, Issue 34 https://doi.org/10.1073/pnas.1100745108	journal	August 2011
EFA6 controls Arf1 and Arf6 activation through a negative feedback loop Padovani, D.; Folly-Klan, M.; Labarde, A. Proceedings of the National Academy of Sciences, Vol. 111, Issue 34 https://doi.org/10.1073/pnas.1409832111	journal	August 2014
N-myristoyltransferase inhibitors as new leads to treat sleeping sickness Frearson, Julie A.; Brand, Stephen; McElroy, Stuart P. Nature, Vol. 464, Issue 7289 https://doi.org/10.1038/nature08893	journal	April 2010
SIRT2 and Lysine Fatty Acylation Regulate the Activity of RalB and Cell Migration Spiegelman, Nicole A.; Zhang, Xiaoyu; Jing, Hui ACS Chemical Biology, Vol. 14, Issue 9 https://doi.org/10.1021/acschembio.9b00492	journal	August 2019
Structural and genomic decoding of human and plant myristoylomes reveals a definitive recognition pattern Castrec, Benoit; Dian, Cyril; Ciccone, Sarah Nature Chemical Biology, Vol. 14, Issue 7 https://doi.org/10.1038/s41589-018-0077-5	journal	June 2018
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

Similar Records

Identification of and Structural Insights into Hit Compounds Targeting N-Myristoyltransferase for Cryptosporidium Drug Development

Journal Article · Mon Sep 18 00:00:00 EDT 2023 · ACS Infectious Diseases · OSTI ID:1619536

Fenwick, Michael K.; Reers, Alexandra R.; Liu, Yi; +11 more

Role of ARF6 in internalization of metal-binding proteins, metallothionein and transferrin, and cadmium-metallothionein toxicity in kidney proximal tubule cells

Journal Article · Tue Jul 01 00:00:00 EDT 2008 · Toxicology and Applied Pharmacology · OSTI ID:1619536

Wolff, Natascha A; Lee, Wing-Kee; Abouhamed, Marouan; +1 more

Altered membrane association of p60v-src and a murine 63-kDa N-myristoyl protein after incorporation of an oxygen-substituted analog of myristic acid

Journal Article · Sat Jul 01 00:00:00 EDT 1989 · Proceedings of the National Academy of Sciences of the United States of America; (USA) · OSTI ID:1619536

Heuckeroth, R O; Gordon, J I

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
Biochemistry
Cell biology
Enzyme mechanisms
Enzymes
Structural biology

Title: NMT1 and NMT2 are lysine myristoyltransferases regulating the ARF6 GTPase cycle

Citation Formats

References (52)

Similar Records

Related Subjects