期刊
SCIENCE SIGNALING
卷 13, 期 640, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.aay5024
关键词
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资金
- NIH [AI118985, R01 GM117424]
- Cellular and Molecular Pharmacology Training Grant [T32 GM007752]
- NHMRC C. J. Martin Early Career Fellowship [1145746]
- Molecular Biophysics Training Grant [T32 GM008326]
- National Health and Medical Research Council of Australia [1145746] Funding Source: NHMRC
Because of their prominent roles in development, cancer, and HIV, the chemokine receptor CXCR4 and its ligand CXCL12 have been the subject of numerous structural and functional studies, but the determinants of ligand binding, selectivity, and signaling are still poorly understood. Here, building on our latest structural model, we used a systematic mutagenesis strategy to dissect the functional anatomy of the CXCR4-CXCL12 complex. Key charge swap mutagenesis experiments provided evidence for pairwise interactions between oppositely charged residues in the receptor and chemokine, confirming the accuracy of the predicted orientation of the chemokine relative to the receptor and providing insight into ligand selectivity. Progressive deletion of N-terminal residues revealed an unexpected contribution of the receptor N terminus to chemokine signaling. This finding challenges a longstanding two-site hypothesis about the essential features of the receptor-chemokine interaction in which the N terminus contributes only to binding affinity. Our results suggest that although the interaction of the chemokine N terminus with the receptor-binding pocket is the key driver of signaling, the signaling amplitude depends on the extent to which the receptor N terminus binds the chemokine. Together with systematic characterization of other epitopes, these data enable us to propose an experimentally consistent structural model for how CXCL12 binds CXCR4 and initiates signal transmission through the receptor transmembrane domain.
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