Abstract
N-terminal acetylation is an abundant modification influencing protein functions. Because ∼80% of mammalian cytosolic proteins are N-terminally acetylated, this modification is potentially an untapped target for chemical control of their functions. Structural studies have revealed that, like lysine acetylation, N-terminal acetylation converts a positively charged amine into a hydrophobic handle that mediates protein interactions; hence, this modification may be a druggable target. We report the development of chemical probes targeting the N-terminal acetylation–dependent interaction between an E2 conjugating enzyme (UBE2M or UBC12) and DCN1 (DCUN1D1), a subunit of a multiprotein E3 ligase for the ubiquitin-like protein NEDD8. The inhibitors are highly selective with respect to other protein acetyl-amide–binding sites, inhibit NEDD8 ligation in vitro and in cells, and suppress anchorage-independent growth of a cell line with DCN1 amplification. Overall, our data demonstrate that N-terminal acetyl-dependent protein interactions are druggable targets and provide insights into targeting multiprotein E2–E3 ligases.
Document Type
Article
Publication Date
8-2017
Digital Object Identifier (DOI)
https://doi.org/10.1038/nchembio.2386
Funding Information
B.A.S., ALSAC, HHMI, and NIH R37GM069530, P30CA021765; J.T.H., NIH F32GM113310; J.W.H., NIH AG011085; J.A.P., NIH DK098285; J.P., NIH GM114260; SJCRH Proteomics Facility, NIH P30CA021765; American Lebanese Syrian Associated Charities.
Related Content
Structural data have been deposited in the Protein DataBank (PDB) with coordinate accession numbers 5V83.pdb (DCN1-NAcM-HIT), 5V86.pdb (DCN1-NAcM-OPT), 5V88.pdb (DCN1:NAcM-COV), 5V89.pdb (DCN4PONY:CUL1WHB). All other data generated or analyzed during this study are included in this published article (and its supplementary information files) or are available from the corresponding author on reasonable request.
Supplementary information is available in the online version of the paper.
Repository Citation
Scott, Daniel C.; Hammill, Jared T.; Min, Jaeki; Rhee, David Y.; Connelly, Michele; Sviderskiy, Vladislav O.; Bhasin, Deepak; Chen, Yizhe; Ong, Su-Sien; Chai, Sergio C.; Goktug, Asli N.; Huang, Guochang; Monda, Julie K.; Low, Jonathan; Kim, Ho Shin; Paulo, Joao A.; Cannon, Joe R.; Shelat, Anang A.; Chen, Taosheng; Kelsall, Ian R.; Alpi, Arno F.; Pagala, Vishwajeeth; Wang, Xusheng; Peng, Junmin; Singh, Bhuvanesh; Harper, J. Wade; Schulman, Brenda A.; and Guy, R. Kiplin, "Blocking an N-Terminal Acetylation-Dependent Protein Interaction Inhibits an E3 Ligase" (2017). Pharmaceutical Sciences Faculty Publications. 133.
https://uknowledge.uky.edu/ps_facpub/133
Supplementary Text and Figures
nchembio.2386-S2.pdf (1222 kB)
Supplementary Note
nchembio.2386-S3.xlsx (104 kB)
Supplementary Data Set 1
nchembio.2386-S4.xlsx (1779 kB)
Supplementary Data Set 2
nchembio.2386-S5.xls (161 kB)
Supplementary Data Set 3
nchembio.2386-S6.xlsx (57 kB)
Supplementary Data Set 4
nchembio.2386-S7.xlsx (248 kB)
Supplementary Data Set 5
nchembio.2386-S8.xlsx (148 kB)
Supplementary Data Set 6
nchembio.2386-S9.xlsx (58 kB)
Supplementary Data Set 7
nchembio.2386-S10.xlsx (6586 kB)
Supplementary Data Set 8
Included in
Amino Acids, Peptides, and Proteins Commons, Cell and Developmental Biology Commons, Pharmacy and Pharmaceutical Sciences Commons
Notes/Citation Information
Published in Nature Chemical Biology, v. 13, issue 8, p. 850-857.
© 2017 Nature America, Inc., part of Springer Nature. All rights reserved.
The copyright holder has granted the permission for posting the article here.
This is a post-peer-review, pre-copyedit version of an article published in Nature Chemical Biology. The final authenticated version is available online at: https://doi.org/10.1038/nchembio.2386