期刊
NATURE CHEMICAL BIOLOGY
卷 14, 期 5, 页码 466-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41589-018-0036-1
关键词
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资金
- NIH [P41 GM103403, S10OD021527]
- US Department of Energy [DE-AC02-06CH11357]
- Canada Foundation for Innovation
- Natural Sciences and Engineering Research Council of Canada
- University of Saskatchewan
- Government of Saskatchewan
- Western Economic Diversification Canada
- National Research Council Canada
- Canadian Institutes of Health Research
- AbbVie [1097737]
- Bayer Pharma AG [1097737]
- Boehringer Ingelheim [1097737]
- Canada Foundation for Innovation [1097737]
- Eshelman Institute for Innovation [1097737]
- Genome Canada through Ontario Genomics Institute [1097737, OGI-055]
- Innovative Medicines Initiative (EU/EFPIA) [ULTRA-DD grant] [1097737, 115766]
- Janssen [1097737]
- Merck KGaA, Darmstadt, Germany [1097737]
- MSD [1097737]
- Novartis Pharma AG [1097737]
- Ontario Ministry of Research, Innovation and Science (MRIS) [1097737]
- Pfizer [1097737]
- Sao Paulo Research Foundation-FAPESP [1097737]
- Takeda [1097737]
- Wellcome [1097737]
- Natural Sciences and Engineering Research Council of Canada (NSERC) [RGPIN-2016-06300]
The N-end rule pathway senses the N-terminal destabilizing residues of degradation substrates for the ubiquitin-proteasome system, whose integrity shields against various human syndromes including cancer and cardiovascular diseases. GID4, a subunit of the ubiquitin ligase GID complex, has been recently identified as the N-recognin of the new branch of the N-end rule pathway responsible for recognizing substrates bearing N-terminal proline residues (Pro/N-degrons). However, the molecular mechanism of GID4-mediated Pro/N-degron recognition remains largely unexplored. Here, we report the first crystal structures of human GID4 alone and in complex with various Pro/N-degrons. Our complex crystal structures, together with biophysical analyses, delineate the GID4-mediated Pro/N-degron recognition mechanism and substrate selection criteria for the Pro/N-end rule pathway. These mechanistic data on the Pro/N-recognin activity of GID4 will serve as a foundation to facilitate the identification of authentic physiological substrates as well as the development of inhibitors of therapeutic values for the Pro/N-end rule pathway.
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