Structure-based prediction of Ras-effector binding affinities and design of "branchegetic" interface mutations.

Protein Binding ras Proteins / genetics Mutation Proteins / metabolism Molecular Dynamics Simulation
AlphaFold FoldX Ras branch pruning edgetics effectors enedgetics homology modeling hub networks

Journal

Structure (London, England : 1993)
ISSN: 1878-4186
Titre abrégé: Structure
Pays: United States
ID NLM: 101087697

Informations de publication

Date de publication:
06 Jul 2023
Historique:
received: 17 11 2022
revised: 28 02 2023
accepted: 14 04 2023
medline: 10 7 2023
pubmed: 12 5 2023
entrez: 11 5 2023
Statut: ppublish

Résumé

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 modeling based on X-ray and AlphaFold2 templates to build structural models for 54 Ras-effector 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.

Identifiants

DOI: 10.1016/j.str.2023.04.007 PMID: 37167973
pubmed: 37167973
pii: S0969-2126(23)00130-2
doi: 10.1016/j.str.2023.04.007
pii:
doi:

Substances chimiques

ras Proteins EC 3.6.5.2
Proteins 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

870-883.e5

Informations de copyright

Copyright © 2023 Elsevier Ltd. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests The authors declare no competing interests.

Auteurs

Philipp Junk (P)

Systems Biology Ireland, School of Medicine, University College Dublin, Dublin 4, Ireland; UCD Charles Institute of Dermatology, School of Medicine, University College Dublin, Dublin 4, Ireland. Electronic address: philipp.junk@ucd.ie.

Christina Kiel (C)

Systems Biology Ireland, School of Medicine, University College Dublin, Dublin 4, Ireland; UCD Charles Institute of Dermatology, School of Medicine, University College Dublin, Dublin 4, Ireland; Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy.

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Classifications MeSH

questionsmedicales.fr › Métabolisme › Liaison aux protéines › Structure-based prediction of Ras-effector...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protéines G › Protéines G monomériques › Protéines G ras › Structure-based prediction of Ras-effector...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Structure-based prediction of Ras-effector...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Structure-based prediction of Ras-effector...
questionsmedicales.fr › Sciences de l'information › Méthodologies informatiques › Simulation numérique › Simulation de dynamique moléculaire › Structure-based prediction of Ras-effector...