Regulating IL-2 Immune Signaling Function Via A Core Allosteric Structural Network.

Autor: Woodward CH; Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, USA; Center for Computational and Genomic Medicine, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA., Solieva SO; Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, USA; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA., Hwang D; Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, USA; Center for Computational and Genomic Medicine, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA., De Paula VS; Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, USA; Center for Computational and Genomic Medicine, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA., Fabilane CS; Translational Tissue Engineering Center, Johns Hopkins School of Medicine, Baltimore, MD, USA; Program in Molecular Biophysics, Johns Hopkins University, Baltimore, MD, USA., Young MC; Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, USA; Center for Computational and Genomic Medicine, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA., Trent T; Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, USA; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA., Teeley EC; Department of Chemical & Biomolecular Engineering, Johns Hopkins School of Medicine, Baltimore, MD, USA., Majumdar A; Biomolecular NMR Center, Johns Hopkins University, Baltimore, MD, USA., Spangler JB; Translational Tissue Engineering Center, Johns Hopkins School of Medicine, Baltimore, MD, USA; Department of Chemical & Biomolecular Engineering, Johns Hopkins School of Medicine, Baltimore, MD, USA; Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore, MD, USA., Bowman GR; Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, USA; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA., Sgourakis NG; Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, USA; Center for Computational and Genomic Medicine, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. Electronic address: nikolaos.sgourakis@pennmedicine.upenn.edu.
Jazyk: angličtina
Zdroj: Journal of molecular biology [J Mol Biol] 2024 Dec 09; Vol. 437 (2), pp. 168892. Date of Electronic Publication: 2024 Dec 09.
DOI: 10.1016/j.jmb.2024.168892
Abstrakt: Human interleukin-2 (IL-2) is a crucial cytokine for T cell regulation, with therapeutic potential in cancer and autoimmune diseases. However, IL-2's pleiotropic effects across different immune cell types often lead to toxicity and limited efficacy. Previous efforts to enhance IL-2's therapeutic profile have focused on modifying its receptor binding sites. Yet, the underlying dynamics and intramolecular networks contributing to IL-2 receptor recognition remain unexplored. This study presents a detailed characterization of IL-2 dynamics compared to two engineered IL-2 mutants, "superkines" S15 and S1, which exhibit biased signaling towards effector T cells. Using NMR spectroscopy and molecular dynamics simulations, we demonstrate significant variations in core dynamic pathways and conformational exchange rates across these three IL-2 variants. We identify distinct allosteric networks and minor state conformations in the superkines, despite their structural similarity to wild-type IL-2. Furthermore, we rationally design a mutation (L56A) in the S1 superkine's core network, which partially reverts its dynamics, receptor binding affinity, and T cell signaling behavior towards that of wild-type IL-2. Our results reveal that IL-2 superkine core dynamics play a critical role in their enhanced receptor binding and function, suggesting that modulating IL-2 dynamics and core allostery represents an untapped approach for designing immunotherapies with improved immune cell selectivity profiles.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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