4jl7 Citations

Structural Insights into Neutrophilic Migration Revealed by the Crystal Structure of the Chemokine Receptor CXCR2 in Complex with the First PDZ Domain of NHERF1.


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.

Articles - 4jl7 mentioned but not cited (3)

  1. Structural insights into neutrophilic migration revealed by the crystal structure of the chemokine receptor CXCR2 in complex with the first PDZ domain of NHERF1. Lu G, Wu Y, Jiang Y, Wang S, Hou Y, Guan X, Brunzelle J, Sirinupong N, Sheng S, Li C, Yang Z. PLoS ONE 8 e76219 (2013)
  2. New conformational state of NHERF1-CXCR2 signaling complex captured by crystal lattice trapping. Jiang Y, Lu G, Trescott LR, Hou Y, Guan X, Wang S, Stamenkovich A, Brunzelle J, Sirinupong N, Li C, Yang Z. PLoS One 8 e81904 (2013)
  3. Protein crystallization: Eluding the bottleneck of X-ray crystallography. Holcomb J, Spellmon N, Zhang Y, Doughan M, Li C, Yang Z. AIMS Biophys 4 557-575 (2017)

Reviews citing this publication (2)

  1. NHERF1 Between Promises and Hopes: Overview on Cancer and Prospective Openings. Centonze M, Saponaro C, Mangia A. Transl Oncol 11 374-390 (2018)
  2. Role of the PDZ-scaffold protein NHERF1/EBP50 in cancer biology: from signaling regulation to clinical relevance. Vaquero J, Nguyen Ho-Bouldoires TH, Clapéron A, Fouassier L. Oncogene 36 3067-3079 (2017)

Articles citing this publication (5)

  1. Structural insights into PDZ-mediated interaction of NHERF2 and LPA(2), a cellular event implicated in CFTR channel regulation. Holcomb J, Jiang Y, Lu G, Trescott L, Brunzelle J, Sirinupong N, Li C, Naren AP, Yang Z. Biochem Biophys Res Commun 446 399-403 (2014)
  2. Crystallographic analysis of NHERF1-PLCβ3 interaction provides structural basis for CXCR2 signaling in pancreatic cancer. Jiang Y, Wang S, Holcomb J, Trescott L, Guan X, Hou Y, Brunzelle J, Sirinupong N, Li C, Yang Z. Biochem Biophys Res Commun 446 638-643 (2014)
  3. A critical role of CXCR2 PDZ-mediated interactions in endothelial progenitor cell homing and angiogenesis. Hou Y, Wu Y, Farooq SM, Guan X, Wang S, Liu Y, Oblak JJ, Holcomb J, Jiang Y, Strieter RM, Lasley RD, Arbab AS, Sun F, Li C, Yang Z. Stem Cell Res 14 133-143 (2015)
  4. Crystal structure of the NHERF1 PDZ2 domain in complex with the chemokine receptor CXCR2 reveals probable modes of PDZ2 dimerization. Holcomb J, Jiang Y, Guan X, Trescott L, Lu G, Hou Y, Wang S, Brunzelle J, Sirinupong N, Li C, Yang Z. Biochem Biophys Res Commun 448 169-174 (2014)
  5. Structural basis of PDZ-mediated chemokine receptor CXCR2 scaffolding by guanine nucleotide exchange factor PDZ-RhoGEF. Spellmon N, Holcomb J, Niu A, Choudhary V, Sun X, Zhang Y, Wan J, Doughan M, Hayden S, Hachem F, Brunzelle J, Li C, Yang Z. Biochem Biophys Res Commun 485 529-534 (2017)