Molecular analysis of the type III interferon complex and its applications in protein engineering.
Journal
Biophysical journal
ISSN: 1542-0086
Titre abrégé: Biophys J
Pays: United States
ID NLM: 0370626
Informations de publication
Date de publication:
07 11 2023
07 11 2023
Historique:
received:
04
08
2023
revised:
28
09
2023
accepted:
29
09
2023
pmc-release:
07
11
2024
medline:
10
11
2023
pubmed:
5
10
2023
entrez:
5
10
2023
Statut:
ppublish
Résumé
Type III interferons (IFNλs) are cytokines with critical roles in the immune system and are attractive therapeutic candidates due to their tissue-specific activity. Despite entering several clinical trials, results have demonstrated limited efficacy and potency, partially attributed to low-affinity protein-protein interactions (PPIs) responsible for receptor complex formation. Subsequently, structural studies of the native IFNλ signaling complexes remain inaccessible. While protein engineering can overcome affinity limitations, tools to investigate low-affinity systems like these remain limited. To provide insights into previous efforts to strengthen the PPIs within this complex, we perform a molecular analysis of the extracellular ternary complexes of IFNλ3 using both computational and experimental approaches. We first use molecular simulations and modeling to quantify differences in PPIs and residue strain fluctuations, generate detailed free energy landscapes, and reveal structural differences between an engineered, high-affinity complex, and a model of the wild-type, low-affinity complex. This analysis illuminates distinct behaviors of these ligands, yielding mechanistic insights into IFNλ complex formation. We then apply these computational techniques in protein engineering and design by utilizing simulation data to identify hotspots of interaction to rationally engineer the native cytokine-receptor complex for increased stability. These simulations are then validated by experimental techniques, showing that a single mutation at a computationally predicted site of interaction between the two receptors increases PPIs and improves complex formation for all IFNλs. This study highlights the power of molecular dynamics simulations for protein engineering and design as applied to the IFNλ family but also presents a potential tool for analysis and engineering of other systems with low-affinity PPIs.
Identifiants
pubmed: 37794680
pii: S0006-3495(23)00623-9
doi: 10.1016/j.bpj.2023.09.021
pmc: PMC10645568
pii:
doi:
Substances chimiques
Interferon Lambda
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4254-4263Subventions
Organisme : NIGMS NIH HHS
ID : R35 GM147179
Pays : United States
Informations de copyright
Copyright © 2023 Biophysical Society. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests at this time.
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