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Structure-based prediction of Ras-effector binding affinities and design of ‘branchegetic’ interface mutations

View ORCID ProfilePhilipp Junk, View ORCID ProfileChristina Kiel
doi: https://doi.org/10.1101/2022.09.04.506480
Philipp Junk
2Systems Biology Ireland, School of Medicine, University College Dublin, Dublin 4, Ireland
3UCD Charles Institute of Dermatology, School of Medicine, University College Dublin, Dublin 4, Ireland
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  • For correspondence: philipp.junk@ucdconnect.ie
Christina Kiel
1Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy
2Systems Biology Ireland, School of Medicine, University College Dublin, Dublin 4, Ireland
3UCD Charles Institute of Dermatology, School of Medicine, University College Dublin, Dublin 4, Ireland
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Summary

Ras is a central cellular hub protein controlling multiple cell fates. How Ras interacts with a variety of potential effector proteins is relatively unexplored, with only some key effectors characterized in great detail. Here, we have used homology modelling based on X-ray and AlphaFold templates to build structural models for 54 Ras-effectors complexes. These models were used to estimate binding affinities using a supervised learning regressor. Furthermore, we systematically introduced Ras ‘branch-pruning’ (or branchegetic) mutations to identify 200 interface mutations that affect the binding energy with at least one of the model structures. The impacts of these branchegetic mutants were integrated into a mathematical model to assess the potential for rewiring interactions at the Ras hub on a systems level. These findings have provided a quantitative understanding of Ras-effector interfaces and their impact on systems properties of a key cellular hub.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted September 05, 2022.
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Structure-based prediction of Ras-effector binding affinities and design of ‘branchegetic’ interface mutations
Philipp Junk, Christina Kiel
bioRxiv 2022.09.04.506480; doi: https://doi.org/10.1101/2022.09.04.506480
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Structure-based prediction of Ras-effector binding affinities and design of ‘branchegetic’ interface mutations
Philipp Junk, Christina Kiel
bioRxiv 2022.09.04.506480; doi: https://doi.org/10.1101/2022.09.04.506480

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