Crystallographic analysis of NHERF1–PLCβ3 interaction provides structural basis for CXCR2 signaling in pancreatic cancer
| Autor: | Yuanyuan Jiang, Xiaoqing Guan, Chunying Li, Joshua Holcomb, Joseph S. Brunzelle, Zhe Yang, Nualpun Sirinupong, Yuning Hou, Laura Trescott, Shuo Wang |
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| Rok vydání: | 2014 |
| Předmět: |
Models
Molecular Scaffold protein Sodium-Hydrogen Exchangers Protein Conformation PDZ domain Phospholipase C beta Biophysics Peptide binding Plasma protein binding Biology Biochemistry Receptors Interleukin-8B Pancreatic tumor Cell Line Tumor Pancreatic cancer medicine Humans Molecular Biology Binding selectivity Binding Sites Crystallography Cell Biology Phosphoproteins medicine.disease Pancreatic Neoplasms medicine.anatomical_structure Models Chemical Pancreas Protein Binding Signal Transduction |
| Zdroj: | Biochemical and Biophysical Research Communications. 446:638-643 |
| ISSN: | 0006-291X |
| DOI: | 10.1016/j.bbrc.2014.03.028 |
| Popis: | The formation of CXCR2–NHERF1–PLCβ3 macromolecular complex in pancreatic cancer cells regulates CXCR2 signaling activity and plays an important role in tumor proliferation and invasion. We previously have shown that disruption of the NHERF1-mediated CXCR2–PLCβ3 interaction abolishes the CXCR2 signaling cascade and inhibits pancreatic tumor growth in vitro and in vivo. Here we report the crystal structure of the NHERF1 PDZ1 domain in complex with the C-terminal PLCβ3 sequence. The structure reveals that the PDZ1–PLCβ3 binding specificity is achieved by numerous hydrogen bonds and hydrophobic contacts with the last four PLCβ3 residues contributing to specific interactions. We also show that PLCβ3 can bind both NHERF1 PDZ1 and PDZ2 in pancreatic cancer cells, consistent with the observation that the peptide binding pockets of these PDZ domains are highly structurally conserved. This study provides an understanding of the structural basis for the PDZ-mediated NHERF1–PLCβ3 interaction that could prove valuable in selective drug design against CXCR2-related cancers. |
| Databáze: | OpenAIRE |
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