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

TY - JOUR

T1 - Blocking an N-terminal acetylation-dependent protein interaction inhibits an E3 ligase

AU - Scott, Daniel C.

AU - Hammill, Jared T.

AU - Min, Jaeki

AU - Rhee, David Y.

AU - Connelly, Michele C.

AU - Sviderskiy, Vladislav O.

AU - Bhasin, Deepak

AU - Chen, Yizhe

AU - Ong, Su-Sien

AU - Chai, Sergio C.

AU - Goktug, Asli N.

AU - Huang, Guochang

AU - Monda, Julie K.

AU - Low, Jonathan

AU - Kim, Ho Shin

AU - Paulo, Joao A.

AU - Cannon, Joe R.

AU - Shelat, Anang A.

AU - Chen, Taosheng

AU - Kelsall, Ian R.

AU - Alpi, Arno F.

AU - Pagala, Vishwajeeth

AU - Wang, Xusheng

AU - Peng, Junmin

AU - Singh, Bhuvanesh

AU - Harper, J. Wade

AU - Schulman, Brenda A.

AU - Guy, R. Kip

N1 - 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.

PY - 2017/6

Y1 - 2017/6

N2 - 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.

AB - 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.

KW - Journal article

KW - Chemical tools

KW - Post-translational modifications

KW - Proteins

KW - Screening

KW - X-ray crystallography

U2 - 10.1038/nchembio.2386

DO - 10.1038/nchembio.2386

M3 - Article

C2 - 28581483

SN - 1552-4450

VL - 13

SP - 850

EP - 857

JO - Nature Chemical Biology

JF - Nature Chemical Biology

IS - 8

ER -