Biology subjects

Olsson, S.

Publications and source records attributed to Olsson, S..

At least 19 recordsLinked to original sources

bioRxiv2026

Rice OsML1, a distant plant homologue of animal MD-2 protein, can also bind to and recognize bacterial LPS and co-triggers innate immunity

Lipopolysaccharides (LPSs) are pathogen-associated molecular patterns (PAMPs) of Gram-negative pathogenic bacteria recognized by plants, triggering typical pattern-triggered immunity (PTI) responses. However, a LPS sensing receptor for the recognition of plants remains largely undefined. A plant receptor for lipopolysaccharide (LPS) has not yet been identified. Here, we identify a plant protein, OsML1, with homologies to animal MD-2, which is capable of binding LPS. Furthermore, it may act as a molecular chaperone to assist CK1 in perceiving LPS signals. Our results show that OsML1 functions as an LPS-binding protein recognizing LPS and participates in downstream rice immune response activation. Structural modeling and sequence analysis revealed that OsML1 contains both a typical ML domain and a conserved three-dimensional {beta}-barrel structure as mammalian MD-2 proteins. Microscale thermophoresis assays confirmed that OsML1 binds LPS with high affinity. Functional analyses further demonstrated that OsML1 knockout plants show reduced resistance to the rice bacterial blight pathogen, as well as attenuated ROS bursts upon LPS treatments, whereas overexpression plants show enhanced immune responses. Metabolomic profiling indicated significant metabolic changes in OsML1 knockout plants, particularly in immune-related pathways involving lipids, amino acids, and antimicrobial compounds. OsML1 is consequently a structurally conserved and functional LPS-binding protein linking lipid metabolism, LPS perception, immune activation, and metabolic regulation. Phylogenetic and structural analyses revealed that OsML1 likely arose from a duplication of OsML2, forming an independently functional subgroup within the PITP family. Our study identifies OsML1 as a LPS recognition factor involved in LPS sensing and downstream ROS bursts activation, callose deposition, and broad-spectrum gene expression of resistance. These findings expand our knowledge of bacterial LPS perception and immune regulation in plants, offering novel targets and strategies for disease-resistant breeding.

plant biology↗

bioRxiv2026

Demographic history shapes forest tree vulnerability to climate change

Demographic history is expected to play a central role in shaping population vulnerability to climate change through its lasting effects on effective population sizes and genetic connectivity. However, existing studies report contrasting outcomes, and the consequences of alternative demographic histories have seldom been assessed concurrently across multiple taxa. Here, we analysed population genomic data from six of the major European forest tree species to address this gap. Across species, genetic isolation reduced adaptive potential, as reflected in lower standing genetic diversity. Greater genetic differentiation was also associated with increased maladaptation to climate, whereas the purge or accumulation of deleterious mutations depended on the severity of past demographic events. Finally, the beneficial effects of gene flow were evidenced across the six species by more optimal climate adaptation in highly connected populations. Altogether, our results provide valuable insights into how genetic differentiation, reflecting the combined effects of genetic drift and limited historical gene flow, influences current vulnerability of forest tree populations to climate change.

evolutionary biology↗

bioRxiv2026

Accelerating multi-objective VHH discovery via integrated high-throughput selection and AlphaFold3-guided structure prediction

Discovering therapeutic antibodies that bind multiple related targets with high affinity and favourable biophysical properties remains challenging and resource intensive. For snakebite antivenoms, this challenge is critical as treatments must neutralise toxins across multiple snake species. We developed a pipeline combining high-throughput yeast screening, deep sequencing, and AlphaFold3 structure prediction to rapidly identify poly-specific variable domains of heavy-chain-only antibodies (VHHs) against long-chain -neurotoxins. Multiplexed yeast display screening generated a dataset of diverse candidates with varying binding specificities. AlphaFold3-generated VHH-toxin complex predictions enabled structure-based prioritisation that accurately predicted poly-specific binders targeting conserved epitopes across multiple toxins. These structural insights enabled computational optimisation of both affinity and solubility without disrupting target recognition. Experimental validation confirmed improved variants maintained broad specificity across toxins. This integrated approach accelerates multi-objective antibody discovery by predicting which candidates will bind multiple targets before extensive laboratory testing, providing a generalisable strategy applicable beyond antivenoms to any therapeutic requiring broad target coverage.

bioengineering↗

bioRxiv2025

Fungal Mst3-proteins are involved in fungal innate immunity needed for the recognition of bacteria surrounding the hyphae, as well as for plant pathogenicity

Fungal innate immunity overall responses are as fast as and resemble mammalian innate immunity. It does not, however, employ membrane toll-like receptors (TLRs), but should employ endocytosis of non-fungal molecular patterns recognized by nuclear-localizing receptors (NLR). Downstream, both types of receptors in mammals are Mammalian Ste20 kinases (MSTs). We identified single MST3 orthologs in the plant pathogens Fusarium graminearum (FgMST3) and Magnaporthe oryzae (MoMST3). We knocked out both genes and investigated mutants using a standard panel of tests for growth, development, and pathogenicity for each respective fungus. Both{Delta} FgMST3 and{Delta} MoMST3 strains showed reduced pathogenicity. The deletions negatively affected conidia production and conidia germination but had little effect on growth rate. However, the two mutants reacted differently to some stress treatments, such as Zn2+ and gentamicin. Furthermore, we constructed an innate immunity reporter system for F. graminearum based on a gene with fast responses to bacterial MAMPs to detect less than 4-hour responses to non-self-molecular patterns (NSMP) like bacterial outer membrane vesicles (OMVs) as well as trace levels of sucrose, as a plant NSMP. The reporter gene responses to OMVs of MST3 mutant strains were severely reduced. Our results suggest that both MoMst3 and FgMst3 are involved in fungal innate immunity downstream of unknown NLR proteins, motivating studies to try to identify genes for the NLR-like receptors. Finding such and investigating how they work and vary between fungal species and strains should be useful for understanding fungal biotic interactions with viruses, bacteria, plants, and animals.

immunology↗

bioRxiv2025

Unravelling the intraspecific variation in drought responses in seedlings of European black pine (Pinus nigra J.F. Arnold)

O_LIUnderstanding intraspecific variation in drought tolerance is essential for predicting the adaptive capacity of forest species under climate change. Yet, the molecular basis of this variation remains poorly understood in ecologically and economically important conifers. C_LIO_LIWe integrated high-throughput phenotyping with metabolomics and transcriptomics under standardized soil drying to investigate drought responses across nine climatically distinct provenances of the conifer Pinus nigra. We tested whether drought tolerance--measured as decline in maximum quantum yield of the photosystem II (Fv/Fm)--varies among provenances, follows a climatic cline, and involves trade-off with growth. To identify the underlying molecular basis, we performed metabolomics and transcriptomics in four provenances representing contrasting drought tolerance. C_LIO_LIDrought tolerance varied significantly among provenances and was decoupled from growth, yet showed no differentiation along the climatic cline. Drought tolerant provenances differed from sensitive ones in both constitutive and drought-induced levels of flavonoid and diterpene metabolites. Transcriptomic profiles further highlighted provenance-specific differences in gene expression related to flavonoids. C_LIO_LIOur results demonstrate the utility of integrating automated phenotyping with molecular profiling to uncover the metabolic basis of drought adaptation, laying the groundwork for targeted studies on metabolite function and tolerance strategies in non-model conifers. C_LI

plant biology↗

bioRxiv2025

The FORGENIUS genomic resources: new genotyping tools and genomic data for 23 forest tree species and their Genetic Conservation Units

Genetic diversity is a critical but often overlooked component of biological diversity. The European H2020 FORGENIUS project is precisely aimed at increasing the quality and quantity of genetic data to start monitoring the European network of forest Genetic Conservation Units (GCUs). A first step in this direction was developing standardized genomic resources for 23 forest tree species, spanning from rare and scattered (e.g., Abies nebrodensis and Torminalis glaberrima) to widespread, economically relevant ones (e.g., Fagus sylvatica, Picea abies and Pinus sylvestris). Here, we describe the development and application of targeted genotyping tools, primarily based on Single Primer Enrichment Technology (SPET), along with existing SNP arrays for the selected species. The SPET panels developed in FORGENIUS were designed to capture {square}10,000 loci per species, balancing species-specific and randomly distributed regions to ensure broad genome coverage and minimize ascertainment bias. Across 7,192 genotyped trees, we identified over 1.8 million single nucleotide polymorphisms (SNPs) covering approximately 50 Mb of DNA sequence. SPET panels demonstrated high genotyping efficiency and cross-species transferability, especially within genera such as Quercus and Abies. They represent a cost-effective, flexible, and scalable solution for population-level genetic assessments across diverse taxa, enabling standardized, genome-wide characterization of the GCU network. These resources not only promote the establishment of genetic monitoring, support genetically informed conservation strategies and improve our understanding of adaptive responses in European forests, but also enhance species delimitation and hybrid detection, and enable the characterization of phylogenetically related but previously underexplored species.

genomics↗

bioRxiv2025

Characterizing structural and kinetic ensembles of intrinsically disordered proteins using writhe

The biological functions of intrinsically disordered proteins (IDPs) are governed by the conformational states they adopt in solution and the kinetics of transitions between these states. We apply writhe, a knot-theoretic measure that quantifies the crossings of curves in three-dimensional space, to analyze the conformational ensembles and dynamics of IDPs. We develop multiscale descriptors of protein backbones from writhe to identify slow motions of IDPs and demonstrate that these descriptors provide a superior basis for constructing Markov state models of IDP conformational dynamics compared to traditional distance-based descriptors. Additionally, we leverage the symmetry properties of writhe to design an equivariant neural network architecture to sample conformational ensembles of IDPs with a denoising diffusion probabilistic model. The writhe-based frameworks presented here provide a powerful and versatile approach for understanding how the structural ensembles and conformational dynamics of IDPs influence their biological functions. Significance StatementIntrinsically disordered proteins (IDPs) are essential for many cellular processes and are implicated in numerous diseases. The biological functions of IDPs are dictated by the populations of the diverse conformational states they adopt in solution and the kinetics of the conformational transitions between these states. Computer simulations are a powerful tool for studying IDPs, but analyzing simulated structural ensembles of IDPs to identify functionally important conformational states and motions remains a significant challenge. In this study, we demonstrate that writhe, a geometric descriptor from the field of knot theory that describes the crossing of curves in space, provides a powerful basis for characterizing the structural ensembles and conformational dynamics of IDPs in atomic detail. Our results provide new tools for unraveling the relationships between IDP sequences, their conformational ensembles, and their biological functions.

biophysics↗

bioRxiv2024

Extinction of innate floral preferences in the pollinator Eristalis tenax

Innate behaviors allow solitary animals to complete essential tasks in the absence of social learning. However, we know little about the degree to which ecologically relevant innate preferences can change. The hoverfly Eristalis tenax, a solitary generalist pollinator, is an ideal model for studying innate behavior in a naturalistic context because its survival depends on the innate ability to identify flowers. Innate behavior in E. tenax has previously been considered inalterable, but we hypothesized that E. tenax can modulate their innate behavior after training in a multimodal sensory context, in contrast to the prior work that employed unimodal sensory cues. To test this, we examined if E. tenax can extinguish an innate proboscis extension response (PER) to a multimodal floral object after undergoing aversive conditioning with quinine, and if flies can acquire PER to an innately unattractive object using sucrose as reinforcement. Finally, we assessed long-term memory retention. Here, we report a complete extinction of the proboscis extension response (PER) to an innately attractive floral object following aversive training. E. tenax can also acquire PER to an innately unattractive object after appetitive training. Flies can retain these memories for days after training, and aversive memories last longer than appetitive memories. Our results contrast with literature stating that innate preferences cannot be extinguished in E. tenax. This could be because our study uses multimodal objects instead of the unimodal stimuli used in previous work. Ultimately, these findings improve our understanding of how animals navigate the uncertainties of dynamic objects in the natural world.

animal behavior and cognition↗

bioRxiv2023

Quantitative Models of Molecular Dynamics from Sparse Simulation and Experimental Data

Long-timescale behavior of proteins is fundamental to many biological processes. Molecular Dynamics (MD) simulations and biophysical experiments are often used to study protein dynamics. However, high computational demands of MD limit what timescales are feasible to study, often missing rare events, which are critical to explain experiments. On the other hand, experiments are limited by low resolution. We present dynamic Augmented Markov models (dynAMMo) to bridge the gap between these data and overcome their respective limitations. For the first time, dynAMMo enables the construction of mechanistic models of slow exchange processes that have been not observed in MD data by integrating dynamic experimental observables. As a consequence, dynAMMo allows us to bypass costly and extensive simulations, yet providing mechanistic insights of the system. Validated with controlled model systems and a well-studied protein, dynAMMo offers a new approach to quantitatively model protein dynamics on long timescales in an unprecedented manner.

biophysics↗

bioRxiv2023

Synchronous effective population size changes and genetic stability of forest trees through glacial cycles

The effect of past environmental changes on the demography and genetic diversity of natural populations remains a contentious issue and has rarely been investigated across multiple, phylogenetically distant species. Here, we performed comparative population genomic analyses and demographic inferences for seven widely distributed and ecologically contrasted European forest tree species based on concerted sampling of 164 populations across their natural ranges. For all seven species, the effective population size, Ne, increased or remained stable over many glacial cycles and up to 15 million years in the most extreme cases. Hence, surprisingly, the drastic environmental changes associated with the Pleistocene glacial cycles have had little impact on the level of genetic diversity of dominant forest tree species, despite major shifts in their geographic ranges. Based on their trajectories of Ne over time, the seven tree species can be divided into three major groups, highlighting the importance of life history and range size in determining synchronous variation in genetic diversity, over time. Altogether, our results indicate that forest trees were able to retain their evolutionary potential over very long periods of time despite strong environmental changes. One-Sentence SummaryPopulation genomic analyses reveal that forest trees retained their evolutionary potential over the Quaternary.

evolutionary biology↗

bioRxiv2022

Transcriptome analysis of protein kinase MoCK2 affect acetyl-CoA metabolism and import of CK2 interacting mitochondrial proteins into mitochondria in rice blast fungus Magnaporthe oryzae

The rice pathogen Magnaporthe oryzae causes severe losses to rice production. Previous studies have shown protein kinase MoCK2 essential for pathogenesis, and this ubiquitous eukaryotic might affect several processes in the fungus needed for infection. To better understand which cellular processes are affected by the MoCK2 activity, we performed a detailed RNAseq analysis of deletions MoCK2-beta1 and beta2 components in relation to the background strain Ku80 and connected this analysis with the abundance of substrates for proteins in a previous pulldown of the essential CKa subunit of CK2 to estimate effects on proteins directly interacting with CK2. The results showed that MoCK2 seriously affected carbohydrate metabolism, fatty acid metabolism, amino acid metabolism and related transporters and reduced acetyl-CoA production. CK2 phosphorylation can affect the folding of proteins and especially the effective formation of protein complexes by intrinsically disordered or mitochondrial import by destabilizing soluble alpha helixes. Upregulated genes found in the pulldown of the b1 and b2 mutants indicate that proteins directly interacting with CK2 are compensatory upregulated depending on their pulldown. A similar correlation was found for mitochondrial proteins. Taken together, the classes of proteins and the change in regulation in the b1 and b2 mutants suggest that CK2 has a central role in mitochondrial metabolism, secondary metabolism, and ROS resistance, in addition to the previously suggested role in the formation of new ribosomes, all processes central to efficient non-self responses as innate immunity. ImportanceThe protein kinase CK2 is highly expressed and essential for plants, animals, and fungi affecting fatty acid-related metabolism. In addition, it directly affects the import of essential mitochondrial proteins into mitochondria. These effects mean CK2 is essential for lipid metabolism and mitochondrial function and, as shown before, crucial for making new translation machinery proteins. Taken together, our new results combined with previous published indicate that CK2 is an essential protein necessary for the capacity to launch efficient innate immunity responses and withstand the negative effect of such responses necessary for general resistance against invading bacteria and viruses as well as to interact with plants and withstand plant immunity responses and kill plant cells. Protein kinase CK2, highly expressed and essential for plants, animals, and fungi, affects fatty acid-related metabolism and mitochondrial proteins, making it essential for the capacity to launch efficient innate immunity responses and plant pathogenicity

microbiology↗

bioRxiv2022

The wheat head blight pathogen Fusarium graminearum recruits facultative endohyphal bacteria from the soil, making the fungal-bacterial holobiont nitrogen-fixing and increasing the fungal pathogenicity

In nature, fungal endophytes often have facultative endohyphal bacteria. Can a fungal pathogen such as Fusarium graminearum, pathogenic on wheat, get facultative endohyphal bacteria from soil (FEB) and how does the FEB affect the fungal phenotype? We constructed a growth system/microcosm that allowed a molecularly well-studied F. graminearum isolate, PH-1, to grow through natural soil and then be re-isolated on a gentamicin-containing medium, allowing endohyphal growth of the bacteria while killing eventual bacteria growing on the agar medium. We had labelled the F. graminearum PH-1 with a His1mCherry gene staining the fungal nuclei fluorescent red to confirm re-isolation of the same isolate we sent through the soil. Through qPCR of the 16SrRNA gene in the bacteria using universal primers combined with qPCR of the mCherry gene of DNA from the re-isolated cultures of the Fg-FEB holobionts growing on gentamicin-containing media, it was found that most of the holobiont isolates contained about 10 16SrRNA genes per fungal mCherry gene. The Fg-FEB holobiont isolates were sub-cultured several times, and the FEB content on lab media was stable. Sequencing the 16SrRNA gene from several Fg-FEB holobiont isolates revealed known endophytic bacteria capable of nitrogen fixation. We compared the pathogenicity of one of the Fg-FEB holobionts Fg-S.maltophilia, with the background without FEB and found that it was more pathogenic than without FEB. We could also show that the bacterial 16SrRNA load per fungal His1mCherry gene inside the wheat stayed the same as in culture. Finally, we tested if the Fg-S.maltophilia was capable of nitrogen fixation and could show that it, on a nitrogen-free medium, formed a dense mycelium containing proteins at similar levels as on regular nitrogen-containing media. Our results could indicate that naturally occurring fungal pathogens outside lab conditions might contain facultative endohyphal bacteria, positively affecting their pathogenicity and ecological fitness.

ecology↗

bioRxiv2022

MoIsw2 activity could be the missing link between adaptation and mutation instrumental for natural adaptation-directed fast evolution (NADFE) of Magnaporthe oryzae

Isw2 proteins are conserved in eukaryotes and are known to bind to DNA and dynamically influence local chromosome condensation close to their DNA binding site in an ATP-dependent manner making genes close to the binding sites more accessible for transcription and repression. A putative MoISW2 gene was deleted with large effects on plant pathogenicity as a result. The gene was complemented and a ChIP-sec was performed to identify binding sites. RNAsec showed effects on the overall regulation of genes along the chromosomes for mutant and background strains and this was compared with RNAseq from 55 downloaded RNA-seq datasets from the same strain and found similar. MoIsw2 binding and activities create genomic regions affected by MoIsw2 with high gene expression variability close to the MoIsw2 binding sites while surrounding regions have lower gene expression variability. The genes affected by the MoIsw2 activity are niche-determinant genes (secreted proteins, secondary metabolites and stress-coping genes) and avirulence genes. We further show that MoIsw2 binding sites with the DNA binding motifs coincide with known transposable elements (TE) making it likely that TE-transposition at the binding sites can affect the transcription profile of M. oryze in a strain-specific manner. We conclude that MoIsw2 is a likely candidate for a master regulator, regulating the dynamic balance between biomass growth genes (like housekeeping genes) and nich-determinant genes important for ecological fitness. Stress-induced TE transposition is together with MoIsw2 activity a likely mechanism creating more mutations and faster evolution of the niche-determinant genes than for housekeeping genes.

evolutionary biology↗

bioRxiv2021

Identification and characterization of 19 predicted Myb-family DNA binding proteins in Magnaporthe oryzae concerning growth, conidiation, and pathogenicity

Proteins with DNA binding Myb domains have been suggested in regulating development and stress responses. Magnaporthe oryzae is considered the most destructive pathogen of rice. We screened the genome for genes with Myb domains encoding since these can be needed for pathogenesis. We found Myb1-19. Only MoMyb1 was previously shown to be involved in pathogenesis. We succeeded in deleting 12 of the other 18 genes. MoMyb2 deletion affected mainly growth, while MoMyb13 or MoMyb15 deletions gave additional defects in conidiation and plant infection. However, RT-qPCR showed that none of the 19 Myb genes are negligibly expressed. Instead, they have different expression profiles hours post-infection when infecting rice plants. Considering this, the unchanged infection phenotype for 9 gene deletions surprised us, and we extended the analysis to expression co-regulation of all 19 Myb proteins and found 5 co-regulated groups of predicted Myb-domain proteins. MoMyb13 or MoMyb15 are discussed and motivated as candidates for further, more detailed studies with aims also outside of plant pathology. Referring to what is found in other eukaryotes, we finally discuss possible redundancy or compensatory regulations for many of the other Myb genes hiding or compensating for the effect of many complete deletions. IMPORTANCEMagnaporthe oryzae is considered the most important rice pathogen limiting rice production. Our study attempts to find all genes encoding a DNA-binding gene family called Myb, and we found 19, many of which have not been studied before. The Myb gene family is suspected to regulate stress responses the pathogen needs to overcome plant defenses. Inhibiting or disturbing these genes, if they are indeed regulatory, can open new ways of controlling the pathogen and learning more about its physiology and ecology.

microbiology↗

bioRxiv2020

A novel microcosm for recruiting inherently competitive biofertilizer-candidate microorganisms from soil environments

Fertilizer phosphorus (P) is both a necessary crop nutrient and finite resource, necessitating the development of innovative solutions for P fertilizer efficiency and recycling in agricultural systems. Myo-inositol hexakisphosphate (phytate) and its lower order derivatives constitute the majority of identified organic P in many soil types and has been shown to accumulate with increasing application of P fertilizer. Phytate is only poorly available to plants, and in alkaline soils it often precipitated as even more unavailable calcium (Ca)-phytate. Incorporating phytase-producing biofertilizers (i.e., microbial-based products with capacity to mineralize phytate) into soil presents a viable and environmentally acceptable way of utilizing P from phytate, whilst reducing the need for mineral P application. Here we present an in-soil microcosm that utilizes precipitated Ca-phytate to recruit microorganisms with degradation activity towards phytate in solum. Our results show both direct and indirect evidence for Ca-phytate mineralization in vitro and in solum. Furthermore, the abundance of bacteria recruited was measured via 16S rRNA gene copy number, as was three genes relating to organic P degradation; phoX and phoD phosphatases and the BPP ({beta}-propeller phytase) gene. Amplicon sequencing as well as BioLog catabolism studies show that microcosm treatments containing the bait Ca-phytate, recruited a different set of microorganisms when compared to controls. These Ca-phytate microcosms recruited mainly Actinobacteria, Firmicutes, and Proteobacteria, and the genus Streptomyces was specifically enriched. We conclude that our microcosm presents an innovative approach for isolating soil microorganisms with the potential to degrade precipitated phytate in solum and represents a new isolation method with the potential to isolate inherently robust biofertilizer candidates directly from target soils.

ecology↗

bioRxiv2020

Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity

Antiviral therapy is urgently needed to combat the coronavirus disease 2019 (COVID-19) pandemic, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The protease inhibitor camostat mesylate inhibits SARS-CoV-2 infection of lung cells by blocking the virus-activating host cell protease TMPRSS2. Camostat mesylate has been approved for treatment of pancreatitis in Japan and is currently being repurposed for COVID-19 treatment. However, potential mechanisms of viral resistance as well as camostat mesylate metabolization and antiviral activity of metabolites are unclear. Here, we show that SARS-CoV-2 can employ TMPRSS2-related host cell proteases for activation and that several of them are expressed in viral target cells. However, entry mediated by these proteases was blocked by camostat mesylate. The camostat metabolite GBPA inhibited the activity of recombinant TMPRSS2 with reduced efficiency as compared to camostat mesylate and was rapidly generated in the presence of serum. Importantly, the infection experiments in which camostat mesylate was identified as a SARS-CoV-2 inhibitor involved preincubation of target cells with camostat mesylate in the presence of serum for 2 h and thus allowed conversion of camostat mesylate into GBPA. Indeed, when the antiviral activities of GBPA and camostat mesylate were compared in this setting, no major differences were identified. Our results indicate that use of TMPRSS2-related proteases for entry into target cells will not render SARS-CoV-2 camostat mesylate resistant. Moreover, the present and previous findings suggest that the peak concentrations of GBPA established after the clinically approved camostat mesylate dose (600 mg/day) will result in antiviral activity.

molecular biology↗

bioRxiv2020

Molecular mechanism of SARS-CoV-2 cell entry inhibition via TMPRSS2 by Camostat and Nafamostat mesylate

The entry of the coronavirus SARS-CoV-2 into human cells can be inhibited by the approved drugs camostat and nafamostat. Here we elucidate the molecular mechanism of these drugs by combining experiments and simulations. In vitro assays confirm the hypothesis that both drugs act by inhibiting the human protein TMPRSS2. As no experimental structure is available, we provide a model of the TMPRSS2 equilibrium structure and its fluctuations by relaxing an initial homology structure with extensive 280 microseconds of all-atom molecular dynamics (MD) and Markov modeling. We describe the binding mode of both drugs with TMPRSS2 in a Michaelis complex (MC) state preceding the formation of a long-lived covalent inhibitory state. We find that nafamostat to has a higher MC population, which in turn leads to the more frequent formation of the covalent complex and thus higher inhibition efficacy, as confirmed in vitro and consistent with previous virus cell entry assays. Our TMPRSS2-drug structures are made public to guide the design of more potent and specific inhibitors.

biophysics↗

bioRxiv2020

Chromosome fusions shape an ancient UV sex chromosome system

Non-recombining sex chromosomes, like the mammalian Y, often lose genes and accumulate transposable elements, a process termed degeneration1,2. The correlation between suppressed recombination and degeneration is clear in animal XY systems1,2, but the absence of recombination is confounded with other asymmetries between the X and Y. In contrast, UV sex chromosomes, like those found in bryophytes, experience symmetrical population genetic conditions3,4. Here we test for degeneration in the bryophyte UV sex chromosome system through genomic comparisons with new female and male chromosome-scale reference genomes of the moss Ceratodon purpureus. We show that the moss sex chromosomes evolved over 300 million years ago and expanded via two chromosomal fusions. Although the sex chromosomes show signs of weaker purifying selection than autosomes, we find suppressed recombination alone is insufficient to drive gene loss on sex-specific chromosomes. Instead, the U and V sex chromosomes harbor thousands of broadly-expressed genes, including numerous key regulators of sexual development across land plants.

evolutionary biology↗