Crystal structure of the NHERF1 PDZ2 domain in complex with the chemokine receptor CXCR2 reveals probable modes of PDZ2 dimerization

• Published in: Biochemical and biophysical research communications 2014-05, Vol.448 (2), p.169-174
• Main Authors: Holcomb, Joshua, Jiang, Yuanyuan, Guan, Xiaoqing, Trescott, Laura, Lu, Guorong, Hou, Yuning, Wang, Shuo, Brunzelle, Joseph, Sirinupong, Nualpun, Li, Chunying, Yang, Zhe
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Binding Sites; Crystallography, X-Ray; CXCR2; Dimerization; Humans; Models, Molecular; Molecular Sequence Data; Neutrophil; NHERF1; PDZ Domains; Phosphoproteins - chemistry; Phosphoproteins - metabolism; Protein Conformation; Protein Multimerization; Receptors, Interleukin-8B - chemistry; Receptors, Interleukin-8B - metabolism; Scaffold protein; Sodium-Hydrogen Exchangers - chemistry; Sodium-Hydrogen Exchangers - metabolism; X-ray crystallography
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2014.04.085

•CXCR2–NHERF1–PLCβ2 complex regulates CXCR2 signaling in neutrophils.•The crystal structure of the NHERF1 PDZ2 domain in complex with CXCR2.•The structure reveals the specificity determinants of PDZ2–CXCR2 interaction.•Two probable modes of PDZ2 dimerization with parallelly oriented CXCR2 peptides.•Provides implications for NHERF1 complex-scaffolding function in neutrophils. The formation of CXCR2–NHERF1–PLCβ2 macromolecular complex in neutrophils regulates CXCR2 signaling and plays a key role in neutrophil chemotaxis and transepithelial neutrophilic migration. However, NHERF1 by itself, with only two PDZ domains, has a limited capacity in scaffolding the multiprotein-complex formation. Here we report the crystal structure of the NHERF1 PDZ2 domain in complex with the C-terminal CXCR2 sequence. The structure reveals that the PDZ2–CXCR2 binding specificity is achieved by numerous hydrogen bonds and hydrophobic contacts with the last four CXCR2 residues contributing to specific interactions. The structure also reveals two probable modes of PDZ2 dimerization where the two canonical ligand-binding pockets are well separated and orientated in a unique parallel fashion. This study provides not only the structural basis for the PDZ-mediated NHERF1–CXCR2 interaction, but also an additional example of how PDZ domains may dimerize, which both could prove valuable in understanding NHERF1 complex-scaffolding function in neutrophils.