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Biochem Pharmacol. 2016 Aug 15;114:53-68. doi: 10.1016/j.bcp.2016.04.007. Epub 2016 Apr 19.

New paradigms in chemokine receptor signal transduction: Moving beyond the two-site model.

Author information

1
Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA. Electronic address: akleist@mcw.edu.
2
Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA. Electronic address: agetschman@mcw.edu.
3
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Ave, Boston, MA 02115, USA. Electronic address: joshua_ziarek@hms.harvard.edu.
4
Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA. Electronic address: amnevins@mcw.edu.
5
Department of Infection and Immunity, Luxembourg Institute of Health, L-4354 Esch-sur-Alzette, Luxembourg. Electronic address: pierre-arnaud.gauthier@lih.lu.
6
Department of Infection and Immunity, Luxembourg Institute of Health, L-4354 Esch-sur-Alzette, Luxembourg. Electronic address: andy.chevigne@lih.lu.
7
Department of Infection and Immunity, Luxembourg Institute of Health, L-4354 Esch-sur-Alzette, Luxembourg. Electronic address: martyna.szpakowska@lih.lu.
8
Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA. Electronic address: bvolkman@mcw.edu.

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.

KEYWORDS:

7TMR activation; Biased agonism; Chemokine stoichiometry; Seven transmembrane-spanning receptor (7TMR); Two-site model

PMID:
27106080
PMCID:
PMC5145291
DOI:
10.1016/j.bcp.2016.04.007
[Indexed for MEDLINE]
Free PMC Article

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