title: Coincidence detection and bi-directional transmembrane signaling control a bacterial second messenger receptor.
abstract: The second messenger c-di-GMP (or cyclic diguanylate) regulates biofilm formation, a physiological adaptation process in bacteria, via a widely conserved signaling node comprising a prototypical transmembrane receptor for c-di-GMP, LapD, and a cognate periplasmic protease, LapG. Previously, we reported a structure-function study of a soluble LapD•LapG complex, which established conformational changes in the receptor that lead to c-di-GMP-dependent protease recruitment (Chatterjee et al., 2014). This work also revealed a basal affinity of c-di-GMP-unbound receptor for LapG, the relevance of which remained enigmatic. Here, we elucidate the structural basis of coincidence detection that relies on both c-di-GMP and LapG binding to LapD for receptor activation. The data indicate that high-affinity for LapG relies on the formation of a receptor dimer-of-dimers, rather than a simple conformational change within dimeric LapD. The proposed mechanism provides a rationale of how external proteins can regulate receptor function and may also apply to c-di-GMP-metabolizing enzymes that are akin to LapD.
authors.affiliation: Department of Molecular Medicine, College of Veterinary Medicine, Cornell University, Ithaca, United States.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Cooley
authors.affiliation: Department of Molecular Medicine, College of Veterinary Medicine, Cornell University, Ithaca, United States.
authors.forename: John P
authors.initials: JP
authors.lastname: O'Donnell
authors.affiliation: Department of Molecular Medicine, College of Veterinary Medicine, Cornell University, Ithaca, United States.
authors.forename: Holger
authors.identifier: 0000-0003-2211-6234
authors.initials: H
authors.lastname: Sondermann
mesh_terms: D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism*; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000378:metabolism; D008954:Models, Biological; D011487:Protein Conformation; D055503:Protein Multimerization; D011551:Pseudomonas fluorescens / Q000378:metabolism / Q000502:physiology*; D053838:Scattering, Small Angle; D015290:Second Messenger Systems; D015398:Signal Transduction
chemical_list: D001426:Bacterial Proteins; C062025:bis(3',5')-cyclic diguanylic acid; D006152:Cyclic GMP
keywords: biofilm formation; biophysics; infectious disease; membrane protein structure; membrane signaling; microbiology; second messenger; structural biology