title: Crystallographic analysis of NHERF1-PLCβ3 interaction provides structural basis for CXCR2 signaling in pancreatic cancer.
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-mediated NHERF1-PLCβ3 interaction that could prove valuable in selective drug design against CXCR2-related cancers.
authors.affiliation: Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Shuo
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Holcomb
authors.affiliation: Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Trescott
authors.affiliation: Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Guan
authors.affiliation: Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Yuning
authors.initials: Y
authors.lastname: Hou
authors.affiliation: Advanced Photon Source, Argonne National Lab, Argonne, IL, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Brunzelle
authors.affiliation: Nutraceuticals and Functional Food Research and Development Center, Prince of Songkla University, Hat-Yai, Songkhla, Thailand.
authors.forename: Nualpun
authors.initials: N
authors.lastname: Sirinupong
authors.affiliation: Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, MI, USA. Electronic address: cl@med.wayne.edu.
authors.forename: Chunying
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, MI, USA. Electronic address: zyang@med.wayne.edu.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Yang
mesh_terms: D001665:Binding Sites; D045744:Cell Line, Tumor; D003461:Crystallography / Q000379:methods; D006801:Humans; D008956:Models, Chemical; D008958:Models, Molecular; D010190:Pancreatic Neoplasms / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D054799:Phospholipase C beta / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure*; D010750:Phosphoproteins / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure*; D011485:Protein Binding; D011487:Protein Conformation; D023063:Receptors, Interleukin-8B / Q000378:metabolism* / Q000648:ultrastructure; D015398:Signal Transduction; D017923:Sodium-Hydrogen Exchangers / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure*
chemical_list: D010750:Phosphoproteins; D023063:Receptors, Interleukin-8B; D017923:Sodium-Hydrogen Exchangers; C093376:sodium-hydrogen exchanger regulatory factor; D054799:Phospholipase C beta
keywords: CXCR2; NHERF1; PLCβ3; Pancreatic cancer; Scaffold protein; X-ray crystallography