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dc.contributor.author
Li, Hongchun
dc.contributor.author
Sharma, Nanaocha
dc.contributor.author
General, Ignacio
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dc.contributor.author
Schreiber, Gideon
dc.contributor.author
Bahar, Ivet
dc.date.available
2018-04-06T14:45:57Z
dc.date.issued
2017-08
dc.identifier.citation
Li, Hongchun; Sharma, Nanaocha; General, Ignacio; Schreiber, Gideon; Bahar, Ivet; Dynamic Modulation of Binding Affinity as a Mechanism for Regulating Interferon Signaling; Academic Press Ltd - Elsevier Science Ltd; Journal Of Molecular Biology; 429; 16; 8-2017; 2571-2589
dc.identifier.issn
0022-2836
dc.identifier.uri
http://hdl.handle.net/11336/41092
dc.description.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.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
Academic Press Ltd - Elsevier Science Ltd
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dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.subject
Conformational Flexibility
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Elastic Network Models
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Interferon Binding Affinity
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Regulation of Cytokine Signaling
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Structural Dynamics
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Otras Ciencias Biológicas
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dc.subject.classification
Ciencias Biológicas
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dc.subject.classification
CIENCIAS NATURALES Y EXACTAS
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dc.title
Dynamic Modulation of Binding Affinity as a Mechanism for Regulating Interferon Signaling
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2018-04-06T14:09:51Z
dc.journal.volume
429
dc.journal.number
16
dc.journal.pagination
2571-2589
dc.journal.pais
Estados Unidos
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dc.description.fil
Fil: Li, Hongchun. University of Pittsburgh; Estados Unidos
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Fil: Sharma, Nanaocha. Weizmann Institute of Science; Israel
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Fil: General, Ignacio. University of Pittsburgh; Estados Unidos. Universidad Nacional de San Martín; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
dc.description.fil
Fil: Schreiber, Gideon. Weizmann Institute of Science; Israel
dc.description.fil
Fil: Bahar, Ivet. University of Pittsburgh; Estados Unidos
dc.journal.title
Journal Of Molecular Biology
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dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1016/j.jmb.2017.06.011
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S0022283617303121
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/https://pubmed.ncbi.nlm.nih.gov/28648616/
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