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Complex structure of the disulfide bond‐dimerized PDZ‐RhoGEF and CXCR2 PDZ‐binding motif: A new mode of PDZ dimerization
Author(s) -
Spellmon Nicholas S,
Holcomb Joshua,
Niu Andrea,
Choudhary Vishakha,
Brunzelle Joseph,
Li Chunying,
Yang Zhe
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.761.21
Subject(s) - pdz domain , microbiology and biotechnology , biology , scaffold protein , signal transduction , chemistry , biochemistry
Eukaryotic cellular mobility is critically dependent on actin organization and remodeling that are masterfully governed through the Rho signaling pathway activated by Rho guanine exchange factors (RhoGEF). PDZ‐RhoGEF is one unique member of the RhoGEF family which possesses a PDZ domain that is known to nucleate cell surface factors to perpetuate signaling for actin organization and cell mobility. However, the role of the PDZ domain of PDZ‐RhoGEF in signaling transduction pathways for cellular mobility is still not well understood. In this study, we identified PDZ‐RhoGEF binds directly to a novel binding partner CXCR2, a G protein coupled receptor which is known to initiate the Rho signaling program for chemotaxis, haptotaxis, cellular growth and tumor invasion. In order to understand the molecular mechanism of binding, we solved the crystal structure of the chimeric complex between the PDZ domain of PDZ‐RhoGEF and the PDZ‐binding motif of CXCR2. This complex structure reveals that the CXCR2 peptide forms an antiparallel β‐sheet against PDZ‐RhoGEF with the carboxyl‐terminal leucine packaging into a deep hydrophobic pocket within the PDZ domain. Unexpectedly, we found a disulfide bond linking the PDZ domain dimer which secures a parallel binding mode of the CXCR2 ligands to the PDZ monomers. To our knowledge, this is the first PDZ dimer structure covalently linked through a disulfide bond and may be a unique feature to PDZ‐RhoGEF family. This new type of dimerization may be important for stabilizing the CXCR2 macromolecular complex and thereby provide swift signaling for cellular mobility and cancer invasion. Support or Funding Information National Heart, Lung, and Blood Institute