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Mutational scans of the chemokine receptors CXCR4 and CCR5 based on bimolecular fluorescence complementation reveal multiple mechanisms for receptor association

ABSTRACT: Mutational scans of the chemokine receptors CXCR4 and CCR5 based on bimolecular fluorescence complementation reveal multiple mechanisms for receptor association

PROVIDER: PRJNA516349 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8469570_1.fastq.gz	Fastqsanger.gz
	SRR8469570_2.fastq.gz	Fastqsanger.gz
	SRR8469571_1.fastq.gz	Fastqsanger.gz
	SRR8469571_2.fastq.gz	Fastqsanger.gz
	SRR8469572_1.fastq.gz	Fastqsanger.gz

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Mutational scans of the chemokine receptors CXCR4 and CCR5 based on bimolecular fluorescence complementation reveal multiple mechanisms for receptor association

Project description:Many G protein-coupled receptors (GPCRs) are found to homo- or hetero-oligomerize, but how and why GPCRs associate remains controversial. The class A chemokine receptors CCR5 and CXCR4 both homo- and heterodimerize with each other, and crystal structures of CXCR4 in inactive conformations have captured dimeric organization. By selecting libraries of CCR5 and CXCR4 variants based on bimolecular fluorescence complementation, we determine how nearly every single amino acid substitution effects homo-associations. We find three mechanisms for chemokine receptor association: (i) non-specific aggregation in the membrane phase enhanced by destabilizing structural mutations, (ii) specific protein-protein dimerization interfaces, and (iii) motifs in the cytoplasmic tails that are hypothesized to promote lipid raft localization, thereby bringing receptors close together at high density. We identify mutations that tease apart the effects of these respective mechanisms, and show that specific dimer organization, despite reducing agonist binding, is necessary for active signaling within the cell.

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Mapping Interaction Sites on Human Chemokine Receptors by Deep Mutational Scanning

Project description:Chemokine receptors CXCR4 and CCR5 regulate white blood cell trafficking, and are engaged by the HIV-1 envelope glycoprotein gp120 during infection. We combine directed evolution of CXCR4 and CCR5 libraries comprising nearly all ~7,000 single amino acid substitutions with deep sequencing to define sequence-fitness landscapes for surface expression and ligand interactions. Functional interaction sites are mapped based on conservation; for example, extracellular residues are conserved for binding HIV-1-blocking antibodies, as expected. Chemokine CXCL12 interacts with residues extending asymmetrically into the CXCR4 ligand-binding cavity, and distal mutations within allosteric and G protein coupling sites are identified that enhance chemokine binding. CCR5 residues conserved for gp120 interactions partially overlap with the chemokine-binding site, and gp120 binding is increased by acidic substitutions in the CCR5 N-terminus and extracellular loops. Furthermore, general features are apparent from sequence patterns, including membrane regions that are intolerant to polar mutations, and deleterious cysteine substitutions within extracellular loops.

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2016-01-14 | E-GEOD-76820 | biostudies-arrayexpress

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