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

5 years ago

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

Joao A Paulo, Guochang Huang, Julie K Monda, Vishwajeeth Pagala, J Wade Harper, Joe R Cannon, Daniel C Scott, Xusheng Wang, Bhuvanesh Singh, Sergio C Chai, Brenda A Schulman, Su-Sien Ong, Arno F Alpi, Ian R Kelsall, Yizhe Chen, Jaeki Min, Vladislav O Sviderskiy, Anang A Shelat, Michele Connelly, Jonathan Low, David Y Rhee, Ho Shin Kim, Asli N Goktug, R Kip Guy, Jared T Hammill, Junmin Peng, Taosheng Chen, Deepak Bhasin

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.

Publisher URL: http://dx.doi.org/10.1038/nchembio.2386

DOI: 10.1038/nchembio.2386