The structural basis of cyclic diguanylate signal transduction by PilZ domains

• Published in: The EMBO journal Vol. 26; no. 24; pp. 5153 - 5166
• Main Authors: Benach, Jordi, Swaminathan, Swarup S, Tamayo, Rita, Handelman, Samuel K, Folta-Stogniew, Ewa, Ramos, John E, Forouhar, Farhad, Neely, Helen, Seetharaman, Jayaraman, Camilli, Andrew, Hunt, John F
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 12-12-2007; Blackwell Publishing Ltd; Nature Publishing Group
• Subjects: allostery; Amino Acid Sequence; Animals; Bacteria; bacterial pathogenesis; Bacterial Proteins - chemistry; Bacterial Proteins - classification; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Binding Sites; Bioinformatics; Cellular biology; CRYSTAL STRUCTURE; Crystallography, X-Ray; cyclic diguanylate (cyclic-di-GMP); Cyclic GMP - analogs & derivatives; Cyclic GMP - chemistry; Cyclic GMP - genetics; Cyclic GMP - metabolism; DIVERSIFICATION; Eubacteria; fluorescence resonance energy transfer; Humans; MATERIALS SCIENCE; MICE; Models, Molecular; Molecular biology; Molecular Conformation; Molecular Sequence Data; national synchrotron light source; Phylogeny; Protein Binding; Protein Structure, Quaternary; Protein Structure, Secondary; Protein Structure, Tertiary; PROTEINS; RESIDUES; Sequence Alignment; Sequence Homology, Amino Acid; Signal Transduction - physiology; Vibrio cholerae; Vibrio cholerae - metabolism; Vibrio cholerae - pathogenicity; X-ray crystallography
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1038/sj.emboj.7601918

The second messenger cyclic diguanylate (c‐di‐GMP) controls the transition between motile and sessile growth in eubacteria, but little is known about the proteins that sense its concentration. Bioinformatics analyses suggested that PilZ domains bind c‐di‐GMP and allosterically modulate effector pathways. We have determined a 1.9 Å crystal structure of c‐di‐GMP bound to VCA0042/PlzD, a PilZ domain‐containing protein from Vibrio cholerae. Either this protein or another specific PilZ domain‐containing protein is required for V. cholerae to efficiently infect mice. VCA0042/PlzD comprises a C‐terminal PilZ domain plus an N‐terminal domain with a similar β‐barrel fold. C‐di‐GMP contacts seven of the nine strongly conserved residues in the PilZ domain, including three in a seven‐residue long N‐terminal loop that undergoes a conformational switch as it wraps around c‐di‐GMP. This switch brings the PilZ domain into close apposition with the N‐terminal domain, forming a new allosteric interaction surface that spans these domains and the c‐di‐GMP at their interface. The very small size of the N‐terminal conformational switch is likely to explain the facile evolutionary diversification of the PilZ domain.