2. Academic Validation
  3. Blocking an N-terminal acetylation-dependent protein interaction inhibits an E3 ligase

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

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.

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