Structural Insights into Neutrophilic Migration Revealed by the Crystal Structure of the Chemokine Receptor CXCR2 in Complex with the First PDZ Domain of NHERF1
Abstract
Neutrophil plays an essential role in host defense against infection, but uncontrolled neutrophilic infiltration can cause inflammation and severe epithelial damage. We recently showed that CXCR2 formed a signaling complex with NHERF1 and PLC-2, and that the formation of this complex was required for intracellular calcium mobilization and neutrophilic transepithelial migration. To uncover the structural basis of the complex formation, we report here the crystal structure of the NHERF1 PDZ1 domain in complex with the C-terminal sequence of CXCR2 at 1.16 Å resolution. The structure reveals that the CXCR2 peptide binds to PDZ1 in an extended conformation with the last four residues making specific side chain interactions. Remarkably, comparison of the structure to previously studied PDZ1 domains has allowed the identification of PDZ1 ligand-specific interactions and the mechanisms that govern PDZ1 target selection diversities. In addition, we show that CXCR2 can bind both NHERF1 PDZ1 and PDZ2 in pulldown experiments, consistent with the observation that the peptide binding pockets of these two PDZ domains are highly structurally conserved. The results of this study therefore provide structural basis for the CXCR2-mediated neutrophilic migration and could have important clinical applications in the prevention and treatment of numerous neutrophil-dependent inflammatory disorders.
- Authors:
-
- Wayne State University, Detroit, MI (United States)
- Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Prince of Songkla University, Hat-Yai, Songkhla (Thailand)
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Biological and Environmental Research (BER); Leukemia Research Foundation; Aplastic Anemia & MDS International Foundation; Elsa U. Pardee Foundation; American Heart Association
- OSTI Identifier:
- 1627642
- Grant/Contract Number:
- AC02-06CH11357
- Resource Type:
- Accepted Manuscript
- Journal Name:
- PLoS ONE
- Additional Journal Information:
- Journal Volume: 8; Journal Issue: 10; Journal ID: ISSN 1932-6203
- Publisher:
- Public Library of Science
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; crystal structure; hydrogen bonding; neutrophils; calcium signaling; drug interactions; glutathione chromatography; protein interactions; chemokines
Citation Formats
Lu, Guorong, Wu, Yanning, Jiang, Yuanyuan, Wang, Shuo, Hou, Yuning, Guan, Xiaoqing, Brunzelle, Joseph, Sirinupong, Nualpun, Sheng, Shijie, Li, Chunying, and Yang, Zhe. Structural Insights into Neutrophilic Migration Revealed by the Crystal Structure of the Chemokine Receptor CXCR2 in Complex with the First PDZ Domain of NHERF1. United States: N. p., 2013.
Web. doi:10.1371/journal.pone.0076219.
Lu, Guorong, Wu, Yanning, Jiang, Yuanyuan, Wang, Shuo, Hou, Yuning, Guan, Xiaoqing, Brunzelle, Joseph, Sirinupong, Nualpun, Sheng, Shijie, Li, Chunying, & Yang, Zhe. Structural Insights into Neutrophilic Migration Revealed by the Crystal Structure of the Chemokine Receptor CXCR2 in Complex with the First PDZ Domain of NHERF1. United States. https://doi.org/10.1371/journal.pone.0076219
Lu, Guorong, Wu, Yanning, Jiang, Yuanyuan, Wang, Shuo, Hou, Yuning, Guan, Xiaoqing, Brunzelle, Joseph, Sirinupong, Nualpun, Sheng, Shijie, Li, Chunying, and Yang, Zhe. Wed .
"Structural Insights into Neutrophilic Migration Revealed by the Crystal Structure of the Chemokine Receptor CXCR2 in Complex with the First PDZ Domain of NHERF1". United States. https://doi.org/10.1371/journal.pone.0076219. https://www.osti.gov/servlets/purl/1627642.
@article{osti_1627642,
title = {Structural Insights into Neutrophilic Migration Revealed by the Crystal Structure of the Chemokine Receptor CXCR2 in Complex with the First PDZ Domain of NHERF1},
author = {Lu, Guorong and Wu, Yanning and Jiang, Yuanyuan and Wang, Shuo and Hou, Yuning and Guan, Xiaoqing and Brunzelle, Joseph and Sirinupong, Nualpun and Sheng, Shijie and Li, Chunying and Yang, Zhe},
abstractNote = {Neutrophil plays an essential role in host defense against infection, but uncontrolled neutrophilic infiltration can cause inflammation and severe epithelial damage. We recently showed that CXCR2 formed a signaling complex with NHERF1 and PLC-2, and that the formation of this complex was required for intracellular calcium mobilization and neutrophilic transepithelial migration. To uncover the structural basis of the complex formation, we report here the crystal structure of the NHERF1 PDZ1 domain in complex with the C-terminal sequence of CXCR2 at 1.16 Å resolution. The structure reveals that the CXCR2 peptide binds to PDZ1 in an extended conformation with the last four residues making specific side chain interactions. Remarkably, comparison of the structure to previously studied PDZ1 domains has allowed the identification of PDZ1 ligand-specific interactions and the mechanisms that govern PDZ1 target selection diversities. In addition, we show that CXCR2 can bind both NHERF1 PDZ1 and PDZ2 in pulldown experiments, consistent with the observation that the peptide binding pockets of these two PDZ domains are highly structurally conserved. The results of this study therefore provide structural basis for the CXCR2-mediated neutrophilic migration and could have important clinical applications in the prevention and treatment of numerous neutrophil-dependent inflammatory disorders.},
doi = {10.1371/journal.pone.0076219},
journal = {PLoS ONE},
number = 10,
volume = 8,
place = {United States},
year = {Wed Oct 02 00:00:00 EDT 2013},
month = {Wed Oct 02 00:00:00 EDT 2013}
}
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Works referencing / citing this record:
Canonical and Noncanonical Sites Determine NPT2A Binding Selectivity to NHERF1 PDZ1
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