Document Detail


Structural and dynamic determinants of type I interferon receptor assembly and their functional interpretation.
MedLine Citation:
PMID:  23046138     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Type I interferons (IFNs) form a network of homologous cytokines that bind to a shared, heterodimeric cell surface receptor and engage signaling pathways that activate innate and adaptive immune responses. The ability of IFNs to mediate differential responses through the same cell surface receptor has been subject of a controversial debate and has important medical implications. During the past decade, a comprehensive insight into the structure, energetics, and dynamics of IFN recognition by its two-receptor subunits, as well as detailed correlations with their functional properties on the level of signal activation, gene expression, and biological responses were obtained. All type I IFNs bind the two-receptor subunits at the same sites and form structurally very similar ternary complexes. Differential IFN activities were found to be determined by different lifetimes and ligand affinities toward the receptor subunits, which dictate assembly and dynamics of the signaling complex in the plasma membrane. We present a simple model, which explains differential IFN activities based on rapid endocytosis of signaling complexes and negative feedback mechanisms interfering with ternary complex assembly. More insight into signaling pathways as well as endosomal signaling and trafficking will be required for a comprehensive understanding, which will eventually lead to therapeutic applications of IFNs with increased efficacy.
Authors:
Jacob Piehler; Christoph Thomas; K Christopher Garcia; Gideon Schreiber
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Review    
Journal Detail:
Title:  Immunological reviews     Volume:  250     ISSN:  1600-065X     ISO Abbreviation:  Immunol. Rev.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-10-10     Completed Date:  2013-02-25     Revised Date:  2014-04-16    
Medline Journal Info:
Nlm Unique ID:  7702118     Medline TA:  Immunol Rev     Country:  England    
Other Details:
Languages:  eng     Pagination:  317-34     Citation Subset:  IM    
Copyright Information:
© 2012 John Wiley & Sons A/S.
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MeSH Terms
Descriptor/Qualifier:
Binding Sites
Endocytosis / immunology
Feedback, Physiological*
Humans
Interferon Type I / chemistry*,  immunology,  metabolism
Models, Molecular
Protein Binding
Protein Multimerization
Protein Structure, Tertiary
Protein Subunits / chemistry*,  immunology,  metabolism
Receptor, Interferon alpha-beta / chemistry*,  immunology,  metabolism
Signal Transduction
T-Lymphocytes / immunology*,  metabolism
Thermodynamics
Grant Support
ID/Acronym/Agency:
R01 AI051321/AI/NIAID NIH HHS
Chemical
Reg. No./Substance:
0/Interferon Type I; 0/Protein Subunits; 156986-95-7/Receptor, Interferon alpha-beta
Comments/Corrections

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