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Capsular Serotyping of Streptococcus pneumoniae Using the Quellung Reaction
Published on: February 24, 2014
Structure of the Large Extracellular Loop of FtsX and Its Interaction with the Essential Peptidoglycan Hydrolase PcsB
Britta E Rued1,2, Martín Alcorlo3, Katherine A Edmonds2
1Department of Biology, Indiana University Bloomington, Bloomington, Indiana, USA.
Insights
New research reveals the structure of FtsX, a key protein in bacterial cell division. Understanding its interaction with PcsB offers a potential new target for developing urgently needed antibiotics against drug-resistant Streptococcus pneumoniae.
Area of Science:
- Microbiology
- Structural Biology
- Drug Discovery
Background:
- Streptococcus pneumoniae causes significant infant and adult mortality and exhibits increasing antibiotic resistance.
- Targeting bacterial cell division, particularly peptidoglycan synthesis and breakdown, is a promising strategy for new antibiotics.
- The FtsEX complex, involving FtsX and FtsE, plays a crucial role in bacterial cell division.
Purpose of the Study:
- To determine the structure of the extracellular loop 1 (ECL1) of FtsX from Streptococcus pneumoniae.
- To elucidate the molecular mechanism of FtsX interaction with the peptidoglycan hydrolase PcsB.
- To assess the importance of the FtsX-PcsB interaction for S. pneumoniae viability and cell division.
Main Methods:
- Nuclear magnetic resonance (NMR) and X-ray crystallography were used to model the structure of FtsX ECL1.
- Biochemical assays were performed to characterize the interaction between FtsX ECL1 and PcsB.
- Genetic manipulation of S. pneumoniae strains was employed to study the function of FtsX mutants.
Main Results:
- The structure of FtsX ECL1 was determined, revealing distinct β-hairpin and α-helical lobes.
- The α-helical lobe of FtsX ECL1 directly interacts with the coiled-coil domain of PcsB.
- Mutations in the α-helical lobe of FtsX are essential for S. pneumoniae viability and proper cell division.
Conclusions:
- FtsX is a vital component of the cell division machinery in S. pneumoniae, regulating peptidoglycan hydrolase activity.
- The interaction between FtsX and PcsB is critical for bacterial cell viability.
- FtsX represents a conserved and attractive target for novel antibiotic development against S. pneumoniae.
Abstract:
Streptococcus pneumoniae is a leading killer of infants and immunocompromised adults and has become increasingly resistant to major antibiotics. Therefore, the development of new antibiotic strategies is desperately needed. Targeting bacterial cell division is one such strategy, specifically by targeting proteins that are essential for the synthesis and breakdown of peptidoglycan. One complex important to this process is FtsEX. FtsEX comprises a cell division-regulating integral membrane protein (FtsX) and a cytoplasmic ATPase (FtsE) that resembles an ATP-binding cassette (ABC) transporter. Here, we present nuclear magnetic resonance (NMR) solution structural and crystallographic models of the large extracellular domain of FtsX, denoted extracellular loop 1 (ECL1). The structure of ECL1 reveals an upper extended β-hairpin and a lower α-helical lobe, each extending from a mixed α-β core. The helical lobe mediates a physical interaction with the peptidoglycan hydrolase PcsB via the coiled-coil domain of PcsB (PscBCC). Characterization of S. pneumoniae strain D39-derived strains harboring mutations in the α-helical lobe shows that this subdomain is essential for cell viability and required for proper cell division of S. pneumoniaeIMPORTANCE FtsX is a ubiquitous bacterial integral membrane protein involved in cell division that regulates the activity of peptidoglycan (PG) hydrolases. FtsX is representative of a large group of ABC3 superfamily proteins that function as "mechanotransmitters," proteins that relay signals from the inside to the outside of the cell. Here, we present a structural characterization of the large extracellular loop, ECL1, of FtsX from the opportunistic human pathogen S.pneumoniae We show the molecular nature of the direct interaction between the peptidoglycan hydrolase PcsB and FtsX and demonstrate that this interaction is essential for cell viability. As such, FtsX represents an attractive, conserved target for the development of new classes of antibiotics.
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