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New paradigms in chemokine receptor signal transduction: Moving beyond the two-site model. Biochem Pharmacol 2016 08 15;114:53-68

Date

04/24/2016

Pubmed ID

27106080

Pubmed Central ID

PMC5145291

DOI

10.1016/j.bcp.2016.04.007

Scopus ID

2-s2.0-84975744621   38 Citations

Abstract

Chemokine receptor (CKR) signaling forms the basis of essential immune cellular functions, and dysregulated CKR signaling underpins numerous disease processes of the immune system and beyond. CKRs, which belong to the seven transmembrane domain receptor (7TMR) superfamily, initiate signaling upon binding of endogenous, secreted chemokine ligands. Chemokine-CKR interactions are traditionally described by a two-step/two-site mechanism, in which the CKR N-terminus recognizes the chemokine globular core (i.e. site 1 interaction), followed by activation when the unstructured chemokine N-terminus is inserted into the receptor TM bundle (i.e. site 2 interaction). Several recent studies challenge the structural independence of sites 1 and 2 by demonstrating physical and allosteric links between these supposedly separate sites. Others contest the functional independence of these sites, identifying nuanced roles for site 1 and other interactions in CKR activation. These developments emerge within a rapidly changing landscape in which CKR signaling is influenced by receptor PTMs, chemokine and CKR dimerization, and endogenous non-chemokine ligands. Simultaneous advances in the structural and functional characterization of 7TMR biased signaling have altered how we understand promiscuous chemokine-CKR interactions. In this review, we explore new paradigms in CKR signal transduction by considering studies that depict a more intricate architecture governing the consequences of chemokine-CKR interactions.

Author List

Kleist AB, Getschman AE, Ziarek JJ, Nevins AM, Gauthier PA, Chevigné A, Szpakowska M, Volkman BF

Author

Brian F. Volkman PhD Professor in the Biochemistry department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Binding Sites
Chemokines
Humans
Models, Molecular
Protein Binding
Protein Processing, Post-Translational
Protein Structure, Tertiary
Receptors, Chemokine
Signal Transduction
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