Format

Send to

Choose Destination
J Mol Biol. 2017 Aug 4;429(16):2571-2589. doi: 10.1016/j.jmb.2017.06.011. Epub 2017 Jun 23.

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

Author information

1
Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
2
Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 76100, Israel.
3
Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA; School of Science and Technology, and CONICET, Universidad Nacional de San Martin, San Martin, Buenos Aires 1650, Argentina.
4
Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 76100, Israel. Electronic address: gideon.schreiber@weizmann.ac.il.
5
Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA. Electronic address: bahar@pitt.edu.

Abstract

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.

KEYWORDS:

conformational flexibility; elastic network models; interferon binding affinity; regulation of cytokine signaling; structural dynamics

PMID:
28648616
PMCID:
PMC5545807
DOI:
10.1016/j.jmb.2017.06.011
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center