Abstract
Author SummaryBacteria have the ability to form surface-attached communities, so-called biofilms, in both free-living environmental habitats and during pathogenic colonization in infectious diseases. Many of the cellular processes contributing to biofilm formation, for example, changes in motility, cell adhesion, and secretion, are regulated by the nucleotide-based second messenger c-di-GMP, which is unique to bacteria. In Pseudomonas fluorescens, there are high levels of c-di-GMP within the bacterial cell when there is plentiful nutrient availability inside the cell, and the c-di-GMP levels determine stable biofilm formation outside the cell. LapD, a transmembrane receptor for intracellular c-di-GMP, communicates changing c-di-GMP levels to the outside of the cell by controlling the stability of the large adhesin protein LapA, which keeps bacteria attached to a surface or to other cells. We conducted X-ray crystallographic analyses of the structure of the intracellular and periplasmic modules of LapD that, in combination with functional studies, including those shown in an accompanying study by Newell et al., reveal the molecular mechanisms regulating receptor function. When phosphate availability is severely restricted, intracellular c-di-GMP levels are low and LapD is in held in an “off” state by an autoinhibitory interaction, which permits the proteolytic processing of LapA, its release from the cell surface, and consequently biofilm dispersal. Conversely, when there are higher phosphate levels in the growth medium, c-di-GMP increases and binds to a cytoplasmic domain of LapD, disrupting the autoinhibitory state and triggering a conformational change that sequesters the periplasmic protease responsible for cleavage of LapA, ultimately yielding stable cell attachment. By revealing key motifs for the regulation of LapD, we have identified similar systems in many other bacterial strains that may control periplasmic protein processing events in a similar fashion.
Highlights
Bacterial biofilms arise from planktonic microbial cells that attach to surfaces and form sessile multicellular communities, a process relevant to their survival in hostile habitats and for bacterial pathogenesis [1]
LapD is autoinhibited with regard to c-di-GMP binding by interactions of the EAL domain with the signaling helix (S helix) and the GGDEF domain
Receptor activation requires the concurrent release of the EAL domain from these interactions and the binding of c-di-GMP, which triggers a conformational change in the output domain from an incompetent to a competent state with regard to LapG binding [29]
Summary
Bacterial biofilms arise from planktonic microbial cells that attach to surfaces and form sessile multicellular communities, a process relevant to their survival in hostile habitats and for bacterial pathogenesis [1]. Functional differentiation events including changes in motility, cell adhesion, and secretion are among the many processes driving bacterial biofilm formation Such a plethora of physiological responses inevitably poses the question of how regulation is achieved, and a nucleotide unique to bacteria, bis-(39–59) cyclic dimeric guanosine monophosphate (c-di-GMP), has emerged as a key signaling molecule in this process [4,5]. C-di-GMP is a monocyclic RNA dinucleotide that functions as an intracellular second messenger exerting control at the transcriptional, translational, and posttranslational levels [6] It is generated from two guanosine triphosphate (GTP) molecules by GGDEF domain–containing diguanylate cyclases, and degraded by phosphodiesterases containing either EAL or HD-GYP protein domains [7,8,9,10]. C-diGMP turnover domains can serve as sensors for the
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