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

Kleist, Andrew B.; Getschman, Anthony E.; Ziarek, Joshua J.; Nevins, Amanda M.; Gauthier, Pierre-Arnaud; Chevigné, Andy; Szpakowska, Martyna; Volkman, Brian F.

doi:10.1016/j.bcp.2016.04.007

Cited by 113 publications

(121 citation statements)

References 228 publications

(328 reference statements)

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“…S10B). Allosteric communication between the N terminus and TM7 on one side and ECL2 on the other side could “pinch” the chemokine receptor together to “seesaw” TM6 inward at the extracellular surface and outward at the intracellular surface (42, 43). Consistent with this activation model, CXCL12 and CX3CL1 act as conduits by linking opposite sides of their receptors.…”

Section: Discussionmentioning

confidence: 99%

Structural basis for chemokine recognition by a G protein–coupled receptor and implications for receptor activation

et al. 2017

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Chemokines orchestrate cell migration for development, immune surveillance, and disease by binding to cell surface heterotrimeric guanine nucleotide–binding protein (G protein)–coupled receptors (GPCRs). The array of interactions between the nearly 50 chemokines and their 20 GPCR targets generates an extensive signaling network to which promiscuity and biased agonism add further complexity. The receptor CXCR4 recognizes both monomeric and dimeric forms of the chemokine CXCL12, which is a distinct example of ligand bias in the chemokine family. We demonstrated that a constitutively monomeric CXCL12 variant reproduced the G protein–dependent and β-arrestin–dependent responses that are associated with normal CXCR4 signaling and lead to cell migration. In addition, monomeric CXCL12 made specific contacts with CXCR4 that are not present in the structure of the receptor in complex with a dimeric form of CXCL12, a biased agonist that stimulates only G protein–dependent signaling. We produced an experimentally validated model of an agonist-bound chemokine receptor that merged a nuclear magnetic resonance–based structure of monomeric CXCL12 bound to the amino terminus of CXCR4 with a crystal structure of the transmembrane domains of CXCR4. The large CXCL12:CXCR4 protein-protein interface revealed by this structure identified previously uncharacterized functional interactions that fall outside of the classical “two-site model” for chemokine-receptor recognition. Our model suggests a mechanistic hypothesis for how interactions on the extracellular face of the receptor may stimulate the conformational changes required for chemokine receptor-mediated signal transduction.

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Section: Discussionmentioning

confidence: 99%

Structural basis for chemokine recognition by a G protein–coupled receptor and implications for receptor activation

et al. 2017

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“…The crystal structures of CX 3 CL1 bound to the viral chemokine receptor US28, 11 the viral chemokine vMIP‐II bound to CXCR4, 12 and the chemokine antagonist [5P7]CCL5 bound to CCR5, 13 and the model of the CXCL12:CXCR4 complex provide an extraordinarily detailed look at the chemokine–CKR interface, including those contacts defined as CRS2 interactions and buried within the receptor binding pocket. These models, however, in addition to emerging functional studies, challenge the simplicity of the two‐step, two‐site paradigm …”

Section: Introductionmentioning

confidence: 99%

Mutational analysis of CCL20 reveals flexibility of N-terminal amino acid composition and length

Riutta

Larsen

Getschman

et al. 2018

Journal of Leukocyte Biology

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Chemokine-chemokine receptor (CKR) interactions are traditionally described by a two-step/two-site mechanism that details the major contact points between chemokine ligands and CKRs leading to ligand recognition and receptor activation. Chemokine recognition site 1 (CRS1) encompasses interactions between the CKR N-terminus and the globular chemokine core. Chemokine recognition site 2 (CRS2) includes interactions between the unstructured chemokine N-terminus and the binding pocket of the receptor. The two-step/two-site paradigm has been an adequate framework to study the intricacies of chemokine:CKR interactions, but emerging studies highlight the limitations of this model. Here, we present studies of CRS2 interactions between the chemokine CCL20 and its cognate receptor CCR6 driven by the hypothesis that CCL20 interacts with CCR6 as described by the two-step/two-site model. CCL20 is a chemokine with an unusually short N-terminus of 5 residues (NH -ASNFD), compared to the average length of 10 residues for chemokine ligands. We have investigated how well CCL20 tolerates manipulation of the N-terminus by monitoring binding affinity of variants and their ability to activate the receptor. We show the CCL20 N-terminus tolerates truncation of up to 3 residues, extension by up to 5 additional residues, and point mutations at 4 of 5 positions with minimal loss of binding affinity and minimal impairment in ability to stimulate calcium mobilization, inositol triphosphate accumulation, chemotaxis, and β-arrestin-2 recruitment. Mutation of the fifth residue, aspartate, to alanine or lysine has a dramatic impact on binding affinity for CCR6 and ligand potency. We postulate CCL20 does not activate CCR6 through the canonical two-step/two-site mechanism of CKR activation.

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“…Broadly speaking, chemokine receptor subsets are expressed on all major immune cells . Like other chemoattractant GPCRs, chemokine receptors primarily couple to Gαi/o proteins, but have been reported to couple to Gαs, Gαq/11, and Gα12/13 …”

Section: Overview Of the Message And Transmittermentioning

confidence: 99%

Decoding the chemotactic signal

Thomas

Kleist

Volkman

2018

Journal of Leukocyte Biology

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From an individual bacterium to the cells that compose the human immune system, cellular chemotaxis plays a fundamental role in allowing cells to navigate, interpret, and respond to their environments. While many features of cellular chemotaxis are shared among systems as diverse as bacteria and human immune cells, the machinery that guides the migration of these model organisms varies widely. In this article, we review current literature on the diversity of chemoattractant ligands, the cell surface receptors that detect and process chemotactic gradients, and the link between signal recognition and the regulation of cellular machinery that allow for efficient directed cellular movement. These facets of cellular chemotaxis are compared among E. coli, Dictyostelium discoideum, and mammalian neutrophils to derive organizational principles by which diverse cell systems sense and respond to chemotactic gradients to initiate cellular migration.

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

Cited by 113 publications

References 228 publications

Structural basis for chemokine recognition by a G protein–coupled receptor and implications for receptor activation

Structural basis for chemokine recognition by a G protein–coupled receptor and implications for receptor activation

Mutational analysis of CCL20 reveals flexibility of N-terminal amino acid composition and length

Decoding the chemotactic signal

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