Biology subjects

Takkouche, A.

Publications and source records attributed to Takkouche, A..

3 recordsLinked to original sources

bioRxiv2026

Evolutionary history of ligand binding by the LRR domain of innate immunity receptors: the story of the TLR2 cavity

Toll-like receptors (TLRs) are vital components of the innate immune system, recognizing both exogenous pathogens signals (PAMPs) and internal stress signals (DAMPs). TLR2 is unique among the human (Homo sapiens) TLR family members, as it contains a large cavity for binding hydrophobic ligands, such as lipoteichoic acid (LTA) and di/triacyl lipopeptides (Pam2/3CSK4). This study analyzed the structural phylogeny of cavity presence in the TLR2 lineage in vertebrates (vTLR) enabled by AI protein structure predictions and explored the potential convergent evolution of similar features in invertebrates (iTLRs). Analysis of AI models of TLR2s shows that this cavity is consistently present in TRL2 orthologs across jawed vertebrates (Gnathostomata). In jawless vertebrates (Cyclostomatha), these cavities were found in lamprey (Petromyzon marinus) TLR2 model, but only in some extant hagfish (Myxini), suggesting an ancestral origin in basal vertebrates followed by lineage-specific losses. TLR2 paralogs were found in several species, with a similar central cavity but potentially different ligand specificities. In silico ligand docking showed Pam2CSK4 binds to this cavity in all TLRs and paralogs consistently, demonstrating the conserved function of the ligand-binding pocket in gram-positive bacteria recognition across TLR2 branches. Changes in the TLR2 cavity size and shape in some vertebrate groups show the evolution of this DAMP recognition mechanism adapted to its respective pathogens. iTLRs form a separate phylogenetic branch with distinct structural features, but in literature some are considered to be TLR2 orthologs. Indeed, TLRs from some species of Helobdella and Ciona, contain a cavity with some similarity to that in the vTLR2 lineage. However, detailed structural comparisons of their location in the LRR domain and the structural details of the models suggest that their cavities have developed independently from that in TLR2s. Smaller cavities are present in other branches of the LRR family, but show different locations, shapes, and features, indicating that the binding of small ligands in the internal cavities within the LRR domains evolved multiple times in the LRR domain family history.

bioinformatics↗

bioRxiv2024

Divergence of the Individual repeats in the leucine-rich repeat domains of human Toll-like receptors explain their diversity and functional adaptations.

Toll-like receptors (TLRs) are best known pattern recognition receptors of innate immunity, detecting a broad range of pathogen-associated molecular patterns (PAMPs), and endogenous danger associated molecular patterns (DAMPs), initiating inflammatory and antimicrobial responses. TLRs contain two specialized domains, a signaling domain (TIR), and a receptor domain composed of tandem repeats of short 20-30 amino acid segments called Leucine-rich Repeats (LRRs). LRR domains, often paired with other domains, are widespread in all kingdoms of life, invariably forming highly similar, solenoid-like three dimensional structures. Despite this structural conservation, LRR domains overall, and receptor domains of TLRs in particular, exhibit remarkable diversity in binding specificity, recognizing diverse ligands such as lipoproteins, nucleic acids, polysaccharides, other proteins and protein complexes. To understand how this conserved scaffold can accommodate such binding diversity, we performed an in-depth analysis of sequential and structural conservation of individual repeats within the LRR domain of each of the ten human TLRs. We demonstrate that the small variations in repeat lengths and local sequence patterns lead to subtle, but critical structural adaptations, such as changes in local curvature, emergence of loops, cavities and interaction interfaces, each contributing to recognition of specific ligands and formation of the receptor complexes. TLR polymorphisms in human populations can further fine-tune the specificity and strength of ligand recognition, influencing how individuals respond to different pathogens and cell damage causing diseases. We show that in most cases the interfaces with the ligands show high level of polymorphism, suggesting a potential for diverse immune responses to infections among human populations while interfaces with other proteins in the receptor complex are more conserved, pointing to the importance of conserving the overall structure of the signaling pathways. By studying how divergence in LRR repeats affects TLRs structure and function, we provide deeper insights into TLR recognition mechanisms, and a better understanding of the mechanism of evolutionary adaptability of immune recognition systems, both along the evolution of vertebrates, and across the human population. Significance statementHuman Toll-like receptors (hTLRs) play a key role in the innate immune response, recognizing diverse danger molecular patterns through their receptor domains, that consist of tandem repeats of a structural unit called a leucine rich repat (LRR). They are also an example of functionally diverse paralogous family where, despite the overall sequence and structure similarity, each member develops its specific function. Our study reveals that subtle modifications of dividual repeats, without disrupting the overall structure of the receptor domain, form secondary patterns defining the functional specificity of each TLR, enabling them to recognize and respond to a broad array of pathogen and disease associated molecular patterns. These findings offer a new perspective on how sequence variability within conserved protein domains can drive functional evolution and adaptation, with implications both for understanding immune receptor functional adaptation and their fast evolution as well as more general problem of functional diversification in paralogous families.

bioinformatics↗

bioRxiv2024

Global atlas of predicted functional domains in Legionella pneumophila Dot/Icm translocated effectors

Legionella pneumophila utilizes the Dot/Icm type IVB secretion system to deliver hundreds of effector proteins inside eukaryotic cells to ensure intracellular replication. Our understanding of the molecular functions of this largest pathogenic arsenal known to the bacterial world remains incomplete. By leveraging advancements in 3D protein structure prediction, we provide a comprehensive structural analysis of 368 L. pneumophila effectors, representing a global atlas of predicted functional domains summarized in a database (https://pathogens3d.org/legionella-pneumophila). Our analysis identified 157 types of diverse functional domains in 287 effectors, including 159 effectors with no prior functional annotations. Furthermore, we identified 35 unique domains in 30 effector models that have no similarity with experimentally structurally characterized proteins, thus, hinting at novel functionalities. Using this analysis, we demonstrate the activity of thirteen domains, including three unique folds, predicted in L. pneumophila effectors to cause growth defects in the Saccharomyces cerevisiae model system. This illustrates an emerging strategy of exploring synergies between predictions and targeted experimental approaches in elucidating novel effector activities involved in infection.

microbiology↗