Aug 21, 2016

Signal transmission through the CXC chemokine receptor 4 (CXCR4) transmembrane helices

Proceedings of the National Academy of Sciences of the United States of America
Melanie P WescottBenjamin J Doranz

Abstract

The atomic-level mechanisms by which G protein-coupled receptors (GPCRs) transmit extracellular ligand binding events through their transmembrane helices to activate intracellular G proteins remain unclear. Using a comprehensive library of mutations covering all 352 residues of the GPCR CXC chemokine receptor 4 (CXCR4), we identified 41 amino acids that are required for signaling induced by the chemokine ligand CXCL12 (stromal cell-derived factor 1). CXCR4 variants with each of these mutations do not signal properly but remain folded, based on receptor surface trafficking, reactivity to conformationally sensitive monoclonal antibodies, and ligand binding. When visualized on the structure of CXCR4, the majority of these residues form a continuous intramolecular signaling chain through the transmembrane helices; this chain connects chemokine binding residues on the extracellular side of CXCR4 to G protein-coupling residues on its intracellular side. Integrated into a cohesive model of signal transmission, these CXCR4 residues cluster into five functional groups that mediate (i) chemokine engagement, (ii) signal initiation, (iii) signal propagation, (iv) microswitch activation, and (v) G protein coupling. Propagation of the signal...Continue Reading

Mentioned in this Paper

Peptide Nucleic Acids
Guanosine
Monoclonal Antibodies
Monoclonal antibodies, antineoplastic
Chemokine receptor D6
Immunofluorescence Assay
Stromal Cell-Derived Factor 1
Molecular Helix
Cxcr4
HEK293 Cells

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