Biology subjects

Tantos, A.

Publications and source records attributed to Tantos, A..

3 recordsLinked to original sources

bioRxiv2026

Positive selection tends to act on exposed extracellular regions and delineate interaction modules targeted by pathogens

Background: Positive selection shapes protein function by favoring amino acid substitutions that increase fitness. Although numerous studies have identified positively selected genes (PSGs), the structural principles underlying residue-level positive selection remain incompletely understood and previous studies have produced conflicting conclusions, particularly regarding the role of intrinsically disordered regions. In order to resolve these issues and to better understand the driving forces underlying positive selection in human proteins in general, we performed a comprehensive analysis on a manually curated, high quality collection of PSGs and positively selected residues (PSRs) as well as on a large-scale PSR dataset restricted to proteins with experimental structures. Results: Human PSRs were significantly enriched in secreted and cell membrane proteins and preferentially localized to extracellular regions, solvent-exposed surfaces, coil structures, and protein-protein interaction interfaces, whereas neither domains nor intrinsically disordered regions showed an enrichment. Spatial clustering analysis reinforced that PSRs accumulate within localized surface patches. Integration of host-pathogen interaction data highlighted that adaptive changes preferentially affect extracellular molecular recognition surfaces, recurrently appearing in certain pathogen-interacting membrane protein families and particular domain types. Additionally, PSRs showed an enrichment in the residues of human-pathogen interaction interfaces that are in direct contact with pathogenic proteins, implying that neutralizing pathogen attacks is one of the driving forces behind the adaptive evolution of human proteins. By analysing human variation data we found that PSRs are enriched in benign but depleted in pathogenic substitutions, extending previous observations that positively selected genes contain elevated levels of missense variation. Notably, PSGs of the large-scale dataset were also enriched among clinical-stage drug targets, suggesting a potential link between positive selection and pharmacological relevance. Conclusion: Together, our results provide a refined structural model of adaptive evolution in human proteins and identify extracellular exposed molecular recognition surfaces and human-pathogen interaction interfaces as recurrent hotspots of positive selection. Our results point to the direction that precise identification of human PSRs could delineate important host-pathogen interfaces that exert evolutionary selection pressure on humans and appoint novel targets with therapeutic potential.

molecular biology↗

bioRxiv2024

Compositional restrictions in the flanking regions give potential specificity and strength boost to binding in short linear motifs

Short linear motif (SLiM)-mediated protein-protein interactions play important roles in several biological processes where transient binding is needed. They usually reside in intrinsically disordered regions (IDRs), which makes them accessible for interaction. Although information about the possible necessity of the flanking regions surrounding the motifs is increasingly available, it is still unclear if there are any generic amino acid attributes that need to be functionally preserved in these segments. Here, we describe the currently known ligand-binding SLiMs and their flanking regions with biologically relevant residue features and analyse them based on their simplified characteristics. Our bioinformatics analysis reveals several important properties in the widely diverse motif environment that presumably need to be preserved for proper motif function, but remained hidden so far. Our results will facilitate the understanding of the evolution of SLiMs, while also hold potential for expanding and increasing the precision of current motif prediction methods. Author summaryProtein-protein interactions between short linear motifs and their binding domains play key roles in several molecular processes. Mutations in these binding sites have been linked to severe diseases, therefore, the interest in the motif research field has been dramatically increasing. Based on the accumulated knowledge, it became evident that not only the short motif sequences themselves, but their surrounding flanking regions also play crucial roles in motif structure and function. Since most of the motifs tend to be located within highly variable disordered protein regions, searching for functionally important physico-chemical properties in their proximity could facilitate novel discoveries in this field. Here we show that the investigation of the motif flanking regions based on different amino acid attributes can provide further information on motif function. Based on our bioinformatics approach we have found so far hidden features that are generally present within certain motif categories, thus could be used as additional information in motif searching methods as well.

bioinformatics↗

bioRxiv2019

WT and A53T α-synuclein systems: Melting Diagram and its new interpretation

Parkinsons disease is connected with abnormal -synuclein (S) aggregation. Energetics of potential barriers governing motions of hydration water is examined. Information about the distributions and heights of potential barriers is gained by a thermodynamical approach. The ratios of the heterogeneous water-binding interfaces measure proteins structural disorder. All S forms possess secondary structural elements though they are intrinsically disordered. Monomers are functional at the lowest potential barriers, where mobile hydration water exists, with monolayer coverage of mobile hydration. The S monomer contains 33% secondary structure and is more compact than a random coil. A53T S monomer has a more open structure than the wild type. Monomers realize all possible hydrogen bonds. Half of the mobile hydration water amount for monomers is missing in S oligomers and S amyloids. Oligomers are ordered by 66%. Mobile water molecules in the first hydration shell of amyloids are the weakest bound compared to other forms. Wild type and A53T amyloids show identical, low-level hydration, and are considered as disordered to 75%.\n\nStatement of SignificanceAggregation of -synuclein into oligomers, amyloid fibrils is a hallmark of Parkinsons disease. A thermodynamic approach provides information on the heterogeneity of protein-water bonds in the wild type and A53T mutant monomers, oligomers, amyloids. This information can be related to ratios of heterogeneous water-binding interfaces, which measure the proteins structural disorder. Both -synuclein monomers are intrinsically disordered. The monomers nevertheless have 33% secondary structure. They are functional as long as mobile water molecules surround them. They realize every possible H-bonds with water. Oligomers are like globular proteins with 66% ordered structure. Amyloids are disordered to 75% and are poorly hydrated with loosely bound water. Their hydration is identical. Oligomers, amyloids have only half as much hydrating mobile water as monomers.

biophysics↗