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Title: Crystallographic analysis of NHERF1–PLCβ3 interaction provides structural basis for CXCR2 signaling in pancreatic cancer

Highlights: • CXCR2–NHERF1–PLCβ3 complex regulates CXCR2 signaling in pancreatic cancer. • The crystal structure of the NHERF1 PDZ1 domain in complex with PLCβ3. • The structure reveals specificity determinants of PDZ1–PLCβ3 interaction. • Endogenous PLCβ3 in pancreatic cancer cells interacts with both PDZ1 and PDZ2. • Structural basis of the PDZ1–PLCβ3 interaction is valuable in selective drug design. - Abstract: 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-mediatedmore » NHERF1–PLCβ3 interaction that could prove valuable in selective drug design against CXCR2-related cancers.« less
Authors:
; ; ; ; ;  [1] ;  [2] ;  [3] ;  [1] ;  [1]
  1. Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, MI (United States)
  2. Advanced Photon Source, Argonne National Lab, Argonne, IL (United States)
  3. Nutraceuticals and Functional Food Research and Development Center, Prince of Songkla University, Hat-Yai, Songkhla (Thailand)
Publication Date:
OSTI Identifier:
22416365
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 446; Journal Issue: 2; Other Information: Copyright (c) 2014 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; CRYSTAL STRUCTURE; DRUGS; IN VITRO; IN VIVO; NEOPLASMS; PANCREAS; PEPTIDES; RESIDUES; SPECIFICITY; X-RAY DIFFRACTION