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

  • Nat Chem Biol. 2017 Aug;13(8):850-857. doi: 10.1038/nchembio.2386.
Daniel C Scott  1  2 ,  Jared T Hammill  3 ,  Jaeki Min  3 ,  David Y Rhee  4 ,  Michele Connelly  3 ,  Vladislav O Sviderskiy  1 ,  Deepak Bhasin  3 ,  Yizhe Chen  3 ,  Su-Sien Ong  3 ,  Sergio C Chai  3 ,  Asli N Goktug  3 ,  Guochang Huang  5 ,  Julie K Monda  1 ,  Jonathan Low  3 ,  Ho Shin Kim  3 ,  Joao A Paulo  4 ,  Joe R Cannon  4 ,  Anang A Shelat  3 ,  Taosheng Chen  3 ,  Ian R Kelsall  6 ,  Arno F Alpi  7 ,  Vishwajeeth Pagala  8 ,  Xusheng Wang  8 ,  Junmin Peng  1  8 ,  Bhuvanesh Singh  5 ,  J Wade Harper  4 ,  Brenda A Schulman  1  2 ,  R Kip Guy  3
Affiliations
  • 1. Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
  • 2. Howard Hughes Medical Institute, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
  • 3. Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
  • 4. Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
  • 5. Laboratory of Epithelial Cancer Biology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
  • 6. MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, UK.
  • 7. Department of Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Martinsried, Germany.
  • 8. St. Jude Proteomics Facility, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
PMID: 28581483 DOI: 10.1038/nchembio.2386
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.