TY - JOUR
T1 - NMT1 and NMT2 are lysine myristoyltransferases regulating the ARF6 GTPase cycle
AU - Kosciuk, Tatsiana
AU - Price, Ian R.
AU - Zhang, Xiaoyu
AU - Zhu, Chengliang
AU - Johnson, Kayla N.
AU - Zhang, Shuai
AU - Halaby, Steve L.
AU - Komaniecki, Garrison P.
AU - Yang, Min
AU - DeHart, Caroline Jane
AU - Thomas, Paul Martin
AU - Kelleher, Neil L.
AU - Christopher Fromme, J.
AU - Lin, Hening
N1 - Funding Information:
This work was supported by NIH/NIDDK (DK107868), NIH/NIGMS (GM098621), HHMI, and NSF GRFP awards. We thank the National Resource for Translational and Developmental Proteomics (supported by NIH P41 GM108569) for help with ARF6 top–down mass spectrometry, Cornell Proteomic and MS Facility for help with ARF6 G2A mass spectrometry, and Jun Young Hong for help with instruments and reagents. Imaging experiments were performed at Cornell BRC-Imaging facility (supported by NIH S10RR025502, NYSTEM C029155 grants), with support of Johanna M. Dela Cruz. ARF6 (pJAF215) and ARF1 (pJAF211) plasmids were a gift from Dr. Gregory Pazour, and mCherry-TFR-20 plasmid was a gift from Dr. Michael Davidson. We are grateful to Maurine Linder, Richard A. Cerione, Benjamin D. Cosgrove, Hui Jing, and Arash Latifkar for helpful discussions and suggestions. This work made use of the Northeastern Collaborative Access Team beamlines, which are funded by the National Institute of General Medical Sciences from the National Institutes of Health (P30 GM124165). The Eiger 16M detector on 24-ID-E beam line is funded by an NIH-ORIP HEI grant (S10OD021527). This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357. Preliminary X-ray crystallography experiments were also performed at the Advanced Light Source (Berkeley Center for Structural Biology, Lawrence Berkeley National Laboratory, DOE Contract No. DE-AC02-05CH11231 and NIH award P30 GM124169) and at the Cornell High Energy Synchrotron Source (CHESS, NSF award DMR-1829070), using the Macromolecular Diffraction at CHESS (MacCHESS, NIH Award GM-124166) facility. This material is based upon work supported by the National Science Foundation Graduate Research Fellowship Program under Grant No. DGE-1650441. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of National Science Foundation.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85080091357&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85080091357&partnerID=8YFLogxK
U2 - 10.1038/s41467-020-14893-x
DO - 10.1038/s41467-020-14893-x
M3 - Article
C2 - 32103017
AN - SCOPUS:85080091357
SN - 2041-1723
VL - 11
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 1067
ER -
