New paradigms in chemokine receptor signal transduction: Moving beyond the two-site model.
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.
Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA. Electronic address: akleist@mcw.edu.
Andrew B
AB
Kleist
Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA. Electronic address: agetschman@mcw.edu.
Anthony E
AE
Getschman
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Ave, Boston, MA 02115, USA. Electronic address: joshua_ziarek@hms.harvard.edu.
Joshua J
JJ
Ziarek
Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA. Electronic address: amnevins@mcw.edu.
Amanda M
AM
Nevins
Department of Infection and Immunity, Luxembourg Institute of Health, L-4354 Esch-sur-Alzette, Luxembourg. Electronic address: pierre-arnaud.gauthier@lih.lu.
Pierre-Arnaud
PA
Gauthier
Department of Infection and Immunity, Luxembourg Institute of Health, L-4354 Esch-sur-Alzette, Luxembourg. Electronic address: andy.chevigne@lih.lu.
Andy
A
Chevigné
Department of Infection and Immunity, Luxembourg Institute of Health, L-4354 Esch-sur-Alzette, Luxembourg. Electronic address: martyna.szpakowska@lih.lu.
Martyna
M
Szpakowska
Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA. Electronic address: bvolkman@mcw.edu.
Brian F
BF
Volkman
D000818:Animals; D001665:Binding Sites; D018925:Chemokines / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D019707:Receptors, Chemokine / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*
D018925:Chemokines; D019707:Receptors, Chemokine
7TMR activation; Biased agonism; Chemokine stoichiometry; Seven transmembrane-spanning receptor (7TMR); Two-site model