Dynamic Modulation of Binding Affinity as a Mechanism for Regulating Interferon Signaling

• Autores: Li, Hongchun; Sharma, Nanaocha; General, Ignacio; Schreiber, Gideon; Bahar, Ivet
• Año de publicación: 2017
• Idioma: inglés
• Tipo de recurso: artículo
• Materia: Conformational Flexibility; Elastic Network Models; Interferon Binding Affinity; Regulation of Cytokine Signaling; Structural Dynamics
• Institución: Consejo Nacional de Investigaciones Científicas y Técnicas

How structural dynamics affects cytokine signaling is under debate. Here, we investigated the dynamics of the type I interferon (IFN) receptor, IFNAR1, and its effect on signaling upon binding IFN and IFNAR2 using a combination of structure-based mechanistic studies, in situ binding, and gene induction assays. Our study reveals that IFNAR1 flexibility modulates ligand-binding affinity, which, in turn, regulates biological signaling. We identified the hinge sites and key interactions implicated in IFNAR1 inter-subdomain (SD1–SD4) movements. We showed that the predicted cooperative movements are essential to accommodate intermolecular interactions. Engineered disulfide bridges, computationally predicted to interfere with IFNAR1 dynamics, were experimentally confirmed. Notably, introducing disulfide bonds between subdomains SD2 and SD3 modulated IFN binding and activity in accordance with the relative attenuation of cooperative movements with varying distance from the hinge center, whereas locking the SD3–SD4 interface flexibility in favor of an extended conformer increased activity.
Fil: Li, Hongchun. University of Pittsburgh; Estados Unidos
Fil: Sharma, Nanaocha. Weizmann Institute of Science; Israel
Fil: General, Ignacio. University of Pittsburgh; Estados Unidos. Universidad Nacional de San Martín; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Schreiber, Gideon. Weizmann Institute of Science; Israel
Fil: Bahar, Ivet. University of Pittsburgh; Estados Unidos