Chemokine Receptor Oligomerization and Allostery

Stephens, Bryan; Handel, Tracy M.

doi:10.1016/b978-0-12-394587-7.00009-9

Cited by 53 publications

(58 citation statements)

References 129 publications

(162 reference statements)

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“…Heterodimerization of this receptor with the ghrelin receptor (GHSR1a) has been shown to impede GHSR activity [43]. The dimerization across the various CXCR4 crystal structures is consistent with reports of CXCR4 homo- and heterodimerization in cells and its possible physiological relevance [44]. These and many other studies have confirmed that dimerization and / or oligomerization play important roles in receptor function.…”

Section: Introductionsupporting

confidence: 71%

Dynamic roles for the N-terminus of the yeast G protein-coupled receptor Ste2p

Uddin

Naider

Becker

2017

Biochimica et Biophysica Acta (BBA) - Biomembranes

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The Saccharomyces cerevisiae α-factor receptor Ste2p has been used extensively as a model to understand the molecular mechanism of signal transduction by G protein-coupled receptors (GPCRs). Single and double cysteine mutants of Ste2p were created and served as surrogates to detect intramolecular interactions and dimerization of Ste2p using disulfide cross-linking methodology. When a mutation was introduced into the phylogenetically conserved tyrosine residue at position 26 (Y26C) in the N-terminus of Ste2p, dimerization was increased greatly. The amount of dimer formed by this Y26C mutant was greatly reduced by ligand binding even though the ligand binding site is far removed from the N-terminus; the lowering of the dimer formation was consistent with a conformational change in the N-terminus of the receptor upon activation. Dimerization was decreased by double mutations Y26C/V109C or Y26C/T114C indicating that Y26 is in close proximity to V109 and T114 of extracellular loop 1 in native Ste2p. Combined with earlier studies, these results indicate previously unrecognized roles for the N-terminus of Ste2p, and perhaps of GPCRs in general, and reveal a specific N-terminus residue or region, that is involved in GPCR signaling, intrareceptor interactions, and receptor dimerization.

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Section: Introductionsupporting

confidence: 71%

Dynamic roles for the N-terminus of the yeast G protein-coupled receptor Ste2p

Uddin

Naider

Becker

2017

Biochimica et Biophysica Acta (BBA) - Biomembranes

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“…Finally, our data do not exclude the possibility that receptor oligomerization contributes to other processes, such as regulation of pharmacology and trafficking of homo-versus heterooligomers (82,83). It may also contribute to the coordination and efficiency of sequential steps in the GPCR lifecycle.…”

Section: Discussionmentioning

confidence: 96%

Stoichiometry and geometry of the CXC chemokine receptor 4 complex with CXC ligand 12: Molecular modeling and experimental validation

Kufareva

Stephens

Holden

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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124

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Chemokines and their receptors regulate cell migration during development, immune system function, and in inflammatory diseases, making them important therapeutic targets. Nevertheless, the structural basis of receptor:chemokine interaction is poorly understood. Adding to the complexity of the problem is the persistently dimeric behavior of receptors observed in cell-based studies, which in combination with structural and mutagenesis data, suggest several possibilities for receptor:chemokine complex stoichiometry. In this study, a combination of computational, functional, and biophysical approaches was used to elucidate the stoichiometry and geometry of the interaction between the CXC-type chemokine receptor 4 (CXCR4) and its ligand CXCL12. First, relevance and feasibility of a 2:1 stoichiometry hypothesis was probed using functional complementation experiments with multiple pairs of complementary nonfunctional CXCR4 mutants. Next, the importance of dimers of WT CXCR4 was explored using the strategy of dimer dilution, where WT receptor dimerization is disrupted by increasing expression of nonfunctional CXCR4 mutants. The results of these experiments were supportive of a 1:1 stoichiometry, although the latter could not simultaneously reconcile existing structural and mutagenesis data. To resolve the contradiction, cysteine trapping experiments were used to derive residue proximity constraints that enabled construction of a validated 1:1 receptor: chemokine model, consistent with the paradigmatic two-site hypothesis of receptor activation. The observation of a 1:1 stoichiometry is in line with accumulating evidence supporting monomers as minimal functional units of G protein-coupled receptors, and suggests transmission of conformational changes across the dimer interface as the most probable mechanism of altered signaling by receptor heterodimers.chemokine receptor | GPCR dimerization | molecular docking | functional complementation | cysteine trapping T he chemokine receptor CXCR4 regulates cell migration during many developmental processes (1, 2). Along with CCR5, it serves as one of the principal coreceptors for HIV entry into leukocytes (3), and is one of the most important chemokine receptors involved in cancer metastasis (4). Stromal-cell derived factor 1 (SDF-1 or CXCL12) was its only known ligand until recently, when CXCR4 was also shown to bind CXCL14 (5) and extracellular ubiquitin (6). Although structures of CXCR4 (7) and CCR5 (8) have been solved with synthetic antagonists, the structural basis for the interaction of CXCR4 (or any other chemokine receptor) with their natural ligands has yet to be determined. Numerous mutagenesis and NMR studies indicate that receptor:chemokine interactions involve two distinct sites (9-12), which has led to a two-site hypothesis of receptor activation (13). The so-called chemokine recognition site 1 (CRS1) (14) includes the N terminus of the receptor interacting with the globular core of the chemokine, whereas chemokine recognition site 2 (CRS2), located within the tra...

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“…Previous studies have suggested that GPCR oligomerization may account for the formation of multiprotein complexes at the cytoplasmic surfaces of the receptors (27,65,66), and indeed, many chemokine receptors have been shown to homo-and hetero-oligomerize in cells (67)(68)(69). Furthermore, five crystal structures of CXCR4 from different space groups all revealed similar dimers (70).…”

Section: -mentioning

confidence: 88%

The Chemokine Receptor CCR1 Is Constitutively Active, Which Leads to G Protein-independent, β-Arrestin-mediated Internalization

Gilliland

Salanga

Kawamura

et al. 2013

Journal of Biological Chemistry

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Background: CCR1 is a chemokine receptor of significant importance in human health, yet little is known about its ligand-independent behavior. Results: CCR1 exhibits constitutive activity leading to basal signaling and ␤-arrestin-mediated receptor internalization. Conclusion: Constitutive activity may enable CCR1 to engage in dual functions of canonical signaling and non-canonical chemokine scavenging. Significance: This may suggest a new function for CCR1 and avenue for drug development.

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Chemokine Receptor Oligomerization and Allostery

Cited by 53 publications

References 129 publications

Dynamic roles for the N-terminus of the yeast G protein-coupled receptor Ste2p

Dynamic roles for the N-terminus of the yeast G protein-coupled receptor Ste2p

Stoichiometry and geometry of the CXC chemokine receptor 4 complex with CXC ligand 12: Molecular modeling and experimental validation

The Chemokine Receptor CCR1 Is Constitutively Active, Which Leads to G Protein-independent, β-Arrestin-mediated Internalization

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