Molecular basis of GID4-mediated recognition of degrons for the Pro/N-end rule pathway
Abstract
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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GID4 features a substrate-binding domain with a deep, enclosed and ligandable pocket that recognizes the amino-terminal proline residue of protein substrates, leading to their proteasomal degradation.
“GID4, the subunit of the GID E3 ligase complex, features a substrate-binding domain with a deep, enclosed and ligandable pocket that recognizes the amino-terminal proline residue of protein substrates, leading to their proteasomal degradation 131,132 .”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [131]
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Targeted protein degradation: expanding the toolbox
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- Authors
- Dong, C., Zhang, H., Li, L., Tempel, W., Loppnau, P., & Min, J.
- Affiliations
- University of Toronto (CA)
- Corresponding author
- Min, Jinrong
- Venue
- Nature Chemical Biology
- Published
- 2018-04-09
- Volume
- 14
- Issue
- 5
- Pages
- 466-473
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- OpenAlex
- W2795376620
- Cited by
- 111
- References
- 55
- Citations by year
- 2026: 10 · 2025: 13 · 2024: 22 · 2023: 11 · 2022: 18 · 2021: 10 · 2020: 12 · 2019: 11 · 2018: 4
- FWCI
- 3.29
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- N-end rule pathway, N-recognin, protein degradation, substrate recognition, substrate selection, ubiquitin-proteasome system, crystal structure
- MeSH terms
- Protein Domains, Cloning, Molecular, Humans, Mutation, Proline, Protein Binding, Protein Processing, Post-Translational, Substrate Specificity, Protein Structure, Secondary, Crystallography, X-Ray, Ubiquitin, Ubiquitin-Protein Ligases, Proteolysis
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