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Published on: January 24, 2025
Structural characterization of Treponema pallidum Tp0225 reveals an unexpected leucine-rich repeat architecture
Raghavendran Ramaswamy1, Simon Houston1, Bianca Loveless1
1Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC V8P 5C2, Canada.
Abstract:
The phylogenetically divergent spirochete bacterium Treponema pallidum subsp. pallidum is the causative agent of syphilis. Central to the capacity of T. pallidum to establish infection is the ability of the pathogen to attach to a diversity of host cells. Many pathogenic bacteria employ leucine-rich repeat (LRR) domain-containing proteins to mediate protein-protein interactions, including attachment to host components and establishment of infection. Intriguingly, T. pallidum expresses only one putative LRR domain-containing protein (Tp0225) with an unknown function. In an effort to ascribe a function to Tp0225, a comprehensive phylogenetic analysis was first performed; this investigation revealed that Tp0225 clusters with the pathogenic clade of treponemes. Its crystal structure was then determined to 2.0 Å resolution using Pt SAD phasing, which revealed a noncanonical architecture containing a hexameric LRR core with a discontinuous β-sheet bridged by solvent molecules. Furthermore, a surface-exposed, hydrophobic pocket, which was found in Tp0225 but is largely absent in canonical LRR domains from other pathogenic bacteria, may serve to coordinate a hydrophobic ligand. Overall, this study provides the first structural characterization of the sole LRR domain-containing protein from T. pallidum and offers insight into the unique molecular landscape of this important human pathogen.
Insights
Treponema pallidum, the syphilis bacterium, has a unique leucine-rich repeat (LRR) protein, Tp0225. Structural analysis reveals a novel hexameric LRR core and a hydrophobic pocket, offering insights into pathogen attachment and infection mechanisms.
Area of Science:
- Microbiology
- Structural Biology
- Pathogen Research
Background:
- Treponema pallidum subsp. pallidum causes syphilis and requires host cell attachment for infection.
- Leucine-rich repeat (LRR) proteins are common in bacterial pathogens for mediating host interactions.
- T. pallidum possesses a single putative LRR protein, Tp0225, whose function remains uncharacterized.
Purpose of the Study:
- To elucidate the function and structural characteristics of the sole LRR domain-containing protein (Tp0225) in Treponema pallidum.
- To understand the molecular basis of T. pallidum's interaction with host cells.
Main Methods:
- Phylogenetic analysis of Tp0225 to determine its evolutionary relationship within treponemes.
- X-ray crystallography to determine the high-resolution crystal structure of Tp0225 (2.0 Å resolution).
- Analysis of structural features, including the LRR core and surface-exposed pockets.
Main Results:
- Phylogenetic analysis placed Tp0225 within the pathogenic clade of treponemes.
- The crystal structure revealed a noncanonical hexameric LRR core with a discontinuous beta-sheet.
- A unique, surface-exposed hydrophobic pocket was identified in Tp0225, potentially binding hydrophobic ligands.
Conclusions:
- This study provides the first structural characterization of T. pallidum's only LRR protein, Tp0225.
- The unique structural features of Tp0225 suggest a specialized role in the pathogen's interaction with the host.
- Understanding Tp0225 offers insights into the molecular mechanisms of syphilis pathogenesis.
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