Separating Actin-Dependent Chemokine Receptor Nanoclustering from Dimerization Indicates a Role for Clustering in CXCR4 Signaling and Function
| Autor: | Carlos Oscar S. Sorzano, Mario Mellado, Juan A. Torreno-Pina, Rubén Barroso, Carlo Manzo, César Santiago, Maria F. Garcia-Parajo, Laura Martínez-Muñoz, Laura Barrio, Graciela Cascio, José Miguel Rodríguez-Frade, Pilar de Lucas, Yolanda R. Carrasco, Eva M. García-Cuesta, Enric Gutierrez, Javier Vargas, Francisco Sánchez-Madrid |
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| Přispěvatelé: | Ministerio de Economía y Competitividad (España), European Commission, Instituto de Salud Carlos III, Fundació Privada Cellex, Generalitat de Catalunya, Consejo Superior de Investigaciones Científicas (España) |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Receptors CXCR4 Chemokine T-Lymphocytes Amino Acid Motifs TIRF Biology Ligands Cell membrane Jurkat Cells 03 medical and health sciences Chemokine receptor GPCR Receptor clustering Cell Movement medicine Animals Humans Live cell imaging Receptor Molecular Biology Actin G protein-coupled receptor Chemokine receptors Cell Membrane Cell Biology Receptor dynamics Actin cytoskeleton Chemokine CXCL12 Single Molecule Imaging Cell biology Single particle tracking Mice Inbred C57BL Actin Cytoskeleton Protein Transport HEK293 Cells 030104 developmental biology medicine.anatomical_structure CD4 Antigens Mutation biology.protein Nanoparticles Chemokines Protein Multimerization Signal Transduction |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname |
| ISSN: | 1097-4164 |
| Popis: | A current challenge in cell motility studies is to understand the molecular and physical mechanisms that govern chemokine receptor nanoscale organization at the cell membrane, and their influence on cell response. Using single-particle tracking and super-resolution microscopy, we found that the chemokine receptor CXCR4 forms basal nanoclusters in resting T cells, whose extent, dynamics, and signaling strength are modulated by the orchestrated action of the actin cytoskeleton, the co-receptor CD4, and its ligand CXCL12. We identified three CXCR4 structural residues that are crucial for nanoclustering and generated an oligomerization-defective mutant that dimerized but did not form nanoclusters in response to CXCL12, which severely impaired signaling. Overall, our data provide new insights to the field of chemokine biology by showing that receptor dimerization in the absence of nanoclustering is unable to fully support CXCL12-mediated responses, including signaling and cell function in vivo This work was supported by grants from the Spanish Ministry of Economy and Competitiveness (SAF 2014-53416-R, SAF 2017-82940-R AEI/FEDER, EU) and the RETICS Program (RD16/0012/0006; RIER), Ministry of Economy and Competitiveness, Severo Ochoa Programme for Centres of Excellence in R&D (SEV-2013-0347; SEV-2015-0522), and Fundación Privada Cellex and Generalitat de Catalunya (CERCA program). L.M.-M. is supported by the COMFUTURO program of the Spanish Research Council General Foundation. |
| Databáze: | OpenAIRE |
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