Biology subjects

Pyrris, Y.

Publications and source records attributed to Pyrris, Y..

6 recordsLinked to original sources

bioRxiv2026

Pre-neuronal origins of monoamine and acetylcholine synthesis and transport

Neuronal architecture is highly modular and individual components can be found in non-neuronal cell types or even neuronless animals, suggesting some functions predate neurons. However, the evolutionary origins of neurotransmitter synthesis, transport and synaptic vesicle biogenesis outside animals remain obscure. To our knowledge, no previous work has systematically addressed the function of neuronal protein homologs outside animals. Our phylogenetic analysis indicates that orthologs of synaptic vesicle (SV) neurotransmitter transporters (SLC18) and synthesis enzymes are widespread in fungi, which, together with animals and sister taxa, form the clade Opisthokonta. Comparing them with their synaptic counterparts can shed light on the emergence of key functions at the animal-fungi split. Here, we combine extensive phylogenetic profiling and statistical analysis with the generation of functional data for these protein families in fungi. We show that monoamine synthesis, orthologous to that of neurons, is present in fungi and places its origin in the opisthokont common ancestor. We also annotate the orthologs of SLC18 transporters showing that they retain an exporter profile and reside predominantly in the endolysosomal system. Building on this observation, we couple deep-learning localization predictions and GO enrichment analysis to show that the phylogenetic context of SVs is lysosomal throughout the Opisthokonta tree, with implications for their phylogenetic origin. In addition, we monitor fungal gene expression in the presence of monoamines showing that they modulate secondary metabolism, hinting at their physiological significance in a neuronless clade. We propose that the machinery associated with neurotransmission originated before animals.

evolutionary biology↗

bioRxiv2026

Gene duplication shaped the origin and evolution of the vertebrate olfactory combinatorial code

Animals read their chemical environment through olfactory receptors, which form part of the class A GPCRs and are the largest gene family devoted to a single function in animals. Each odorant molecule activates a different combination of receptors, projects distinctly in the brain, and so yields a distinct odour percept. The principles of this coding are well described, and the evolution and regulation of these genes are actively researched. However, how the code was initially assembled and evolved has not been examined. Here we combine phylogenetics, receptor-ligand interactions predicted by paired protein and chemical language models, ancestral sequence reconstruction, and chemical-space analysis. Predicted activation profiles group odorants into six clusters -each enriched for its own set of odour descriptors- so that molecules read by similar receptor combinations tend to smell alike. Reconstructed ancestors place the origin of the code at the first duplication of the family, in the gnathostome ancestor, at the class I/class II split. The first duplicates then diverged asymmetrically into distinct chemical subspaces. One kept a third of the ancestral ligands; the other re-tuned almost completely and took up carboxylic acids -the polar chemistry long associated with class I. Aromatics were retained and enriched on the class II side. Combinatorial coding was not really invented: it arose once, at the first duplication, and was never lost.

evolutionary biology↗

bioRxiv2025

Expansion, functional diversification and gene fusion events in the Ato protein family

Candida albicans, a commensal opportunistic pathogen, exhibits remarkable metabolic flexibility and adaptability to environmental changes. In glucose-limited niches, it utilizes alternative carbon sources such as carboxylic acids, which may influence its pathogenicity. In Saccharomyces cerevisiae, the uptake of monocarboxylates occurs through regulated plasma membrane (PM) transport proteins, such as Ato1 (Ady2), which belongs to the Acetate Uptake Transporter (AceTr) family. In C. albicans, these proteins are notably expanded, consisting of ten Ato-like proteins (ATO1-ATO10), whose functions remain unknown. Here, we investigated the role of Ato proteins in carboxylic acid utilization by C. albicans using in-silico and functional analysis. Our data revealed that several C. albicans Atos retain conserved AceTr motifs but possess distinct structural features, including differences in pore radius and binding sites for acetate and lactate. Expression analysis revealed that Ato1, Ato2, Ato3, and Ato6 exhibit distinct cellular localization and expression levels on the plasma membrane, depending on the presence or absence of monocarboxylates. Remarkably, deletion of ATO1 impaired Ato2 and Ato3 expression and caused ER retention of a distinct form of Ato2, suggesting a central regulatory role for Ato1 in the Ato transport system. Finally, we identified a novel Ato-related protein family in vertebrates. This family has three consecutive 6-helix transport domains and a unique C-terminal fusion with Sua5/YciO/YrdC, an enzyme involved in tRNA modification. Overall, our data suggests that the Ato protein family might play a critical role in the utilization of acetic or lactic acids in C. albicans. It also proposes potential functional redundancy among its members, which may contribute to rapid environmental adaptation and pathogenicity.

microbiology↗

bioRxiv2024

High-resolution structures of the UapA purine transporter reveal unprecedented aspects of the elevator-type transport mechanism.

UapA is an extensively studied elevator-type purine transporter from the model fungus Aspergillus nidulans. Determination of a 3.6[A] inward-facing crystal structure lacking the cytoplasmic N-and C-tails, molecular dynamics (MD), and functional studies have led to speculative models of its transport mechanism and determination of substrate specificity. Here, we report full-length cryo-EM structures of UapA in new inward-facing apo- and substrate-loaded conformations at 2.05-3.5 [A] in detergent and lipid nanodiscs. The structures reveal in an unprecedented level of detail the role of water molecules and lipids in substrate binding, specificity, dimerization, and activity, rationalizing accumulated functional data. Unexpectedly, the N-tail is structured and interacts with both the core and scaffold domains. This finding, combined with mutational and functional studies and MD, points out how N-tail interactions couple proper subcellular trafficking and transport activity by wrapping UapA in a conformation necessary for ER-exit and but also critical for elevator-type conformational changes associated with substrate translocation once UapA has integrated into the plasma membrane. Our study provides detailed insights into important aspects of the elevator-type transport mechanism and opens novel issues on how the evolution of extended cytosolic tails in eukaryotic transporters, apparently needed for subcellular trafficking, might have been integrated into the transport mechanism.

biophysics↗

bioRxiv2022

Transmembrane helices 5 and 12 control transport dynamics, substrate affinity and specificity in the elevator-type UapA transporter

An increasing number of solute transporters have been shown to function with the so-called sliding-elevator mechanism. Despite structural and functional differences all elevator-type transporters use a common mechanism of substrate translocation via reversible movements of a mobile core domain (the elevator) hosting the substrate binding site along a rigid scaffold domain stably anchored in the plasma membrane via homodimerization. One of the best studied elevator transporters is the UapA uric acid-xanthine/H+ symporter of the filamentous fungus Aspergillus nidulans. Here, we present a novel genetic analysis for deciphering the role of transmembrane segments (TMS) 5 and 12 in UapA transport function. We show that specific residues in both TMS5 and TMS12 control, negatively or positively, the dynamics of transport, but also substrate binding affinity and specificity. More specifically, mutations in TMS5 can lead to increased rate of transport, but also to an inactive transporter due to high-affinity substrate-trapping, whereas mutations in TMS12 lead to apparently uncontrolled sliding, and thus broadened specificity and UapA-mediated purine toxicity. Our findings shed new light on how elevator transporters function or how their transport characteristics might be altered genetically or have been modified in the course of evolution.

genetics↗

bioRxiv2022

Molecular basis of uracil/H+ symport mechanism operated by the FurE/NCS1 transporter

Transporters mediate the uptake of solutes, metabolites and drugs across the cell membrane. The eukaryotic FurE nucleobase/H+ symporter of Aspergillus nidulans has been used as a model protein to address structure-function relationships in the APC transporter superfamily, members of which are characterized by the LeuT-fold and seem to operate by the so-called rocking-bundle mechanism. In this study, we reveal the binding mode, translocation and release pathway of uracil/H+ by FurE, using path collective variable, funnel metadynamics and rationally designed mutational analysis. Our study reveals a step-wise, induced-fit, mechanism of ordered sequential transport of proton and uracil, which in turn suggests that the FurE symporter, and probably structurally similar transporters, functions as a multi-step gated pore, rather than employing rocking of compact domains, as generally proposed for APC transporters. In addition, our work further supports the emerging concept that specific elements of cytosolic terminal regions of transporters might be functionally important.

molecular biology↗