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A novel family of channel-forming, autotransporting, bacterial virulence factors
1Department of Biology, University of California at San Diego, La Jolla 92093-0116, USA.
Abstract:
Pathogenic bacteria produce virulence factors that cross the bacterial cell envelope from the cytoplasm to the extracellular milieu where they promote disease. The mechanisms of their export are poorly understood. We here characterize a family of autotransporter (AT) protein domains present at the C-termini of several nonhomologous Gram-negative bacterial virulence factors. The family consist of 18 sequenced protein domains, the functionally characterized members of which catalyze export of (1) proteases, (2) virulence-related cell adhesins, (3) mediators of actin-promoted bacterial motility, (4) cytotoxins and (5) tissue invasion proteins. We (1) establish that these AT domains are homologous, (2) multiply align their sequences, (3) derive an AT family-specific signature sequence, and (4) define the evolutionary relationships between members of the family. Secondary structural predictions as well as average hydropathy, average similarity and average amphipathicity plots have allowed us to propose a specific 14 beta-stranded barrel structural model that may be applicable to all protein members of the AT family. We suggest that the AT domains became associated with active virulence factor domains by interdomain fusion events that occurred during the evolution of these complex proteins.
Insights
Researchers identified a homologous family of autotransporter (AT) protein domains in Gram-negative bacteria. These domains are crucial for exporting various virulence factors, aiding bacterial pathogenesis.
Area of Science:
- Microbiology
- Molecular Biology
- Structural Biology
Background:
- Pathogenic bacteria utilize virulence factors to cause disease.
- The export mechanisms of these bacterial virulence factors across the cell envelope are not well understood.
- Autotransporter (AT) protein domains are found in various Gram-negative bacterial virulence factors.
Purpose of the Study:
- To characterize a family of AT protein domains.
- To understand the homology, evolutionary relationships, and structural model of these AT domains.
- To elucidate the role of AT domains in the export of bacterial virulence factors.
Main Methods:
- Sequence analysis of 18 AT protein domains.
- Multiple sequence alignment and phylogenetic analysis.
- Secondary structure prediction and hydropathy/amphipathicity plotting.
- Development of a structural model for AT domains.
Main Results:
- Established homology among the studied AT domains.
- Derived a conserved AT family signature sequence.
- Defined evolutionary relationships within the AT domain family.
- Proposed a 14 beta-stranded barrel structural model for AT domains.
- Identified AT domains mediating the export of proteases, adhesins, cytotoxins, and invasion proteins.
Conclusions:
- The characterized AT domains represent a homologous family crucial for virulence factor export.
- A conserved structural model and evolutionary relationships were defined for this AT family.
- Interdomain fusion events likely contributed to the evolution of these complex virulence proteins.