Hui Fana,1, Yihu Donga,1, Donghui Wua,1, Matthew W Bowlerb,c, Lianhui Zhanga,2 and Haiwei Songa,d,e,2
a - Institute of Molecular and Cell Biology, Singapore.
b - European Molecular Biology Laboratory, Grenoble Outstation, Grenoble, France.
c - Unit of Virus Host-Cell Interactions, Univ. Grenoble Alpes-EMBL-CNRS, Grenoble, France .
d - Life Sciences Institute, Zhejiang University, Hangzhou, China.
- Department of Biochemistry, National University of Singapore, Singapore.
1. These authors contributed equally to this work
2. Correspondence should be addressed to Haiwei Song (firstname.lastname@example.org)
or Lianhui Zhang (email@example.com)
Published online in PNAS on 6 December 2013.
The human pathogen Pseudomonas aeruginosa coordinates the expression of virulence factors by using quorum sensing (QS), a signaling cascade triggered by the QS signal molecule and its receptor LasR. The QS threshold and response in Pseudomonas aeruginosa is defined by a novel antiactivator, QslA, which binds to LasR and prevents it from binding to its target promoter. However, how QslA binds to LasR and regulates its DNA binding activity in QS remains elusive. Here, we report the crystal structure of QslA in complex with the N-terminal ligand binding domain (LBD) of LasR. QsIA exists as a functional dimer to interact with the LasR LBD. Further analysis shows that QsIA binding occupies the LasR dimerization interface and consequently disrupts LasR dimerization, thereby preventing LasR from binding to its target DNA and disturbing normal QS. Our findings provide a structural model for understanding the QslA-mediated antiactivation mechanism in QS through protein-protein interaction.
Figure Legend: Cells delaminate from the non-neural ectoderm before the neural ectoderm in chicken embryos. The overall structure of the QslA-LasR LBD complex. (A) Two QslA molecules bind to one LasR LBD
in solution, giving rise to a 2:1 binding stoichiometry. Sedimentation velocity analysis of the
QslA-LasR LBD complex in solution at two concentrations (0.4 mg/ml and 0.8 mg/ml) was carried
out and fitted based on the c(M) and c(S) size-distribution functions. The c(S) and c(M) distribution
profile at both concentrations is similar and a representative profile is shown at a concentration
of 0.4 mg/ml. (B) Structure of the QslA-LasR LBD complex. The LasR LBD subunit (Chain A) is shown
in green while the dimeric QslA molecules are shown in light blue (Chain E) and in cyan (Chain F).
The autoinducer 3-oxo-C12-HSL is shown as a stick model.
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