Signal transmission through the CXC chemokine receptor 4 (CXCR4) transmembrane helices
| Autor: | Tracy M. Handel, Melanie P. Wescott, Irina Kufareva, Jason R. Goodman, Bridget A. Puffer, Cheryl Paes, Yana Thaker, Eli Berdougo, Benjamin J. Doranz, Joseph Rucker |
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| Rok vydání: | 2016 |
| Předmět: |
Models
Molecular 0301 basic medicine Receptors CXCR4 Protein Conformation C-C chemokine receptor type 7 C-C chemokine receptor type 6 Biology Ligands 03 medical and health sciences Chemokine receptor Humans Amino Acid Sequence CXC chemokine receptors G protein-coupled receptor Binding Sites Multidisciplinary Sequence Homology Amino Acid Biological Sciences Ligand (biochemistry) Chemokine CXCL12 Cell biology Transmembrane domain HEK293 Cells 030104 developmental biology Chemokine binding Biochemistry Mutation Protein Multimerization Protein Binding Signal Transduction |
| Zdroj: | Proceedings of the National Academy of Sciences. 113:9928-9933 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | 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 passes through a "hydrophobic bridge" on helix VI that coordinates with nearly every known GPCR signaling motif. Our results agree with known conserved mechanisms of GPCR activation and significantly expand on understanding the structural principles of CXCR4 signaling. |
| Databáze: | OpenAIRE |
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