TY - JOUR
T1 - New paradigms in chemokine receptor signal transduction
T2 - Moving beyond the two-site model
AU - Kleist, Andrew B.
AU - Getschman, Anthony E.
AU - Ziarek, Joshua J.
AU - Nevins, Amanda M.
AU - Gauthier, Pierre Arnaud
AU - Chevigné, Andy
AU - Szpakowska, Martyna
AU - Volkman, Brian F.
N1 - Funding Information:
This manuscript was supported by National Institutes of Health (NIH) grant F30CA196040-01A1 (ABK), R01AI058072 (BFV), K99GM115814 (JZZ), the Luxembourg Institute of Health (LIH) grants MESR 20100708 and 20150415 (AC), the “Fonds National de la Recherche” ( FNR ) Luxembourg grants AFR CX-CRP-7 ( 3004509 ) (MS) and AFR CX-CRP-4 ( 5907281 ) (PAG), INTER Nanokine ( 10358798 ) (AC and MS) and F.R.S.-FNRS-Télévie grants CX-CRP-3 ( 7456814 ) and CX-CRP-73 ( 7461515 ) (AC).
Publisher Copyright:
© 2016
PY - 2016/8/15
Y1 - 2016/8/15
N2 - 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.
AB - 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.
KW - 7TMR activation
KW - Biased agonism
KW - Chemokine stoichiometry
KW - Seven transmembrane-spanning receptor (7TMR)
KW - Two-site model
UR - http://www.scopus.com/inward/record.url?scp=84975744621&partnerID=8YFLogxK
U2 - 10.1016/j.bcp.2016.04.007
DO - 10.1016/j.bcp.2016.04.007
M3 - Review article
C2 - 27106080
AN - SCOPUS:84975744621
SN - 0006-2952
VL - 114
SP - 53
EP - 68
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
ER -