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Title: Blocking an N-terminal acetylation–dependent protein interaction inhibits an E3 ligase

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.

Authors:
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Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE
OSTI Identifier:
1375360
Resource Type:
Journal Article
Resource Relation:
Journal Name: Nature Chemical Biology; Journal Volume: 13; Journal Issue: 8
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

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. Kip. Blocking an N-terminal acetylation–dependent protein interaction inhibits an E3 ligase. United States: N. p., 2017. Web. doi:10.1038/nchembio.2386.
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., & Guy, R. Kip. Blocking an N-terminal acetylation–dependent protein interaction inhibits an E3 ligase. United States. doi:10.1038/nchembio.2386.
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. Kip. Mon . "Blocking an N-terminal acetylation–dependent protein interaction inhibits an E3 ligase". United States. doi:10.1038/nchembio.2386.
@article{osti_1375360,
title = {Blocking an N-terminal acetylation–dependent protein interaction inhibits an E3 ligase},
author = {Scott, Daniel C. and Hammill, Jared T. and Min, Jaeki and Rhee, David Y. and Connelly, Michele and Sviderskiy, Vladislav O. and Bhasin, Deepak and Chen, Yizhe and Ong, Su-Sien and Chai, Sergio C. and Goktug, Asli N. and Huang, Guochang and Monda, Julie K. and Low, Jonathan and Kim, Ho Shin and Paulo, Joao A. and Cannon, Joe R. and Shelat, Anang A. and Chen, Taosheng and Kelsall, Ian R. and Alpi, Arno F. and Pagala, Vishwajeeth and Wang, Xusheng and Peng, Junmin and Singh, Bhuvanesh and Harper, J. Wade and Schulman, Brenda A. and Guy, R. Kip},
abstractNote = {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.},
doi = {10.1038/nchembio.2386},
journal = {Nature Chemical Biology},
number = 8,
volume = 13,
place = {United States},
year = {Mon Jun 05 00:00:00 EDT 2017},
month = {Mon Jun 05 00:00:00 EDT 2017}
}