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Rewiring protein binding specificity in paralogous DRG/DFRP complexes
Open accessPreprint — published as 10.1016/j.str.2024.08.012
Abstract
Summary: The Developmentally Regulated GTP-binding (DRG) proteins are an ancient subfamily of GTPases implicated in the regulation of translation and cell growth. In eukaryotes, there are two paralogs: DRG1 and DRG2, both of which have a conserved binding partner called DRG family regulatory protein 1 and 2 (DFRP1 and DFRP2), respectively. These binding partners are required for the function of DRGs, including their stabilisation at the protein level. Moreover, DFRPs interact with their respective DRG via a conserved region called the DFRP domain. Despite being highly similar, DRG1 and DRG2 have strict binding specificity for their respective DFRP. Using AlphaFold generated structure models of the human DRG/DFRP complexes, we have biochemically characterised their interactions and identified interface residues involved in determining specificity. This analysis revealed that as few as five mutations in DRG1 are able to switch its binding from DFRP1 to DFRP2. We show how two DRG1 residues in the core of the interface are most important for specifying the interaction with DFRP1 over DFRP2. We also demonstrate that whilst DFRP1 can stimulate the GTPase activity of DRG1, DFRP2 binding cannot. Overall, this work provides new insight into the structural determinants responsible for the binding specificities of the DRG:DFRP translation factor complexes, which are known to be essential for normal development in mice and humans.
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Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764
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Metadata
- Authors
- Westrip, C. A. E., Smerdon, S. J., & Coleman, M. L.
- Affiliations
- University of Birmingham (GB)
- Corresponding author
- Westrip, Christian A. E.
- Coleman, Mathew L.
- Venue
- Structure
- Publisher
- openRxiv
- Published
- 2023-06-02
- Volume
- 32
- Issue
- 11
- Pages
- 2049-2062.e4
- ISSN
- 0969-2126 (ISSN-L)
- OpenAlex
- W4402515360
- Cited by
- 2
- References
- 1
- Citations by year
- 2026: 1 · 2025: 1
- FWCI
- 0.27
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Structure (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (publishedVersion, cc-by)
- University of Birmingham Research Portal (University of Birmingham) (publishedVersion, cc-by)
- Funders
- Cancer Research UK (C33483/A2567)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- DRG1, interface residues, GTPase activity, protein stability
- MeSH terms
- Amino Acid Sequence, Binding Sites, Humans, Models, Molecular, Mutation, Nerve Tissue Proteins, Protein Binding, GTP-Binding Proteins, Protein Stability
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