Biology subjects

Srinivasan, B.

Publications and source records attributed to Srinivasan, B..

11 recordsLinked to original sources

bioRxiv2026

When should a pathogen strike? Navigating the landscape of birth pulses and mating season

Susceptibility to pathogens often differs across host life stages, which in turn depends on seasonal host phenology. For many species, juveniles are highly susceptible relative to adults, which given constrained birth periods can lead to seasonal variation in the average host susceptibility. Similarly, for pathogens with complex lifecycles, or seasonally dependent development, peak transmission may be temporally constrained. Maximum pathogen transmission may therefore coincide with a greater abundance of either juvenile or adult hosts. For instance, the birthing season presents a highly susceptible pool of hosts while the mating season presents a higher rate of contact between potentially less susceptible hosts. When these two transmission opportunities are separated in time, it is unclear whether pathogens should evolve a single, intermediate transmission timing or undergo disruptive selection to exploit different host life stages. To investigate how pathogens might navigate this complex landscape, we developed an age-structured model that allows us to test the impacts of host life history on pathogen prevalence and evolution, inspired by a fungal plant pathogen. Parameterizing the model for Silene latifolia, we find that disease prevalence is highest when seed germination coincides with flowering, and that separating the two reduces disease. Using invasion analysis, we find that at the estimated S. latifolia parameters, a single evolutionarily stable transmission timing closely tracks germination time, with infectious flowering centered about seven weeks after the median germination day. When juveniles mature faster or are much more susceptible than adults, or under parameters for Dianthus pavonius, a pathogen genotype that transmits to spring-germinating juveniles and one that transmits later in the year can instead each invade the other and coexist as a polymorphic population when germination is split between spring and summer cohorts. Our model may help explain observed phenological differences seen in wild populations of infected plants.

evolutionary biology↗

bioRxiv2026

The human metabolite - protein interactome reveals a global layer of cellular coordination

Metabolites are substrates, products, cofactors, and regulators, but protein-protein interaction networks do not represent their potential to organize proteins across conventional pathway boundaries. Using the LIGMAP virtual-screening algorithm, we mapped 308 human metabolite codes to pockets in monomers, dimer interfaces, and non-interface sites in dimers and represented attractive or repulsive COLIG states involving pairs of metabolites in the same pocket. On a fixed cohort of 3,938 proteins, the mean coverage of 104 strict non-enzyme pathways was 44.6% for LIGMAP, 70.1% for STRING, and 82.5% for STRING+LIGMAP; the union placed 86.3% of eligible proteins in the largest connected component and 95.1% in the two largest components. STRING+LIGMAP protein coverage was 88.0% for 68 enzyme-only pathways and 88.9% for 1,283 mixed pathways. In pathway-held-out, degree-matched prediction, adding LIGMAP to degree plus STRING increased the mean area under the precision-recall curve from 0.651 to 0.660 (paired P = 0.024); adding BioLiP2 increased it to 0.663 (paired P = 0.005). Ancient-only and non-ancient-only subnetworks were each globally connected; ancient features were denser, whereas non-ancient features covered more proteins and pathways. At the full 5,426-protein scale, retaining only features assigned to 2-100 proteins recovered 698 of 1,691 strict non-enzyme reference edges (41.3%) and exceeded both protein-label and exact bipartite degree-preserving nulls. Uncapped recovery approached saturation and lost identity-selective enrichment. Experimentally established metabolite-dependent complexes validate the local mechanism independently of LIGMAP; LIGMAP fully recovered two of seven stringent direct mechanisms and all three broader serial axes examined. Our findings reveal a global metabolite-mediated architecture with the capacity to coordinate proteins across otherwise distinct cellular systems.

bioinformatics↗

bioRxiv2026

Metabolites form a globally connected chemical network across protein families

Metabolites are generally viewed as substrates, products, cofactors, or regulators of individual proteins, whereas metabolites recurring across many protein families are often regarded as promiscuous binders. Here, we analyzed 989,058 BioLiP2 protein-ligand binding sites and assigned 929,546 sites to ECOD v295 homologous groups to quantify ligand specificity, cross-fold scatter, structural breadth, and metabolite-mediated connectivity across protein-family space. Many ancient metabolites preferentially occupied cognate structural groups, demonstrating that broad evolutionary reuse can coexist with local structural discrimination. After excluding elemental metals, BioLiP potential-artifact/dual-use ligands, and metabolites containing fewer than six heavy atoms, 32 ancient metabolites occupied a mean of 185.38 ECOD F-groups per metabolite, compared with 6.32 F-groups for 2,540 mapped filtered non-ancient metabolites-- a 29.35-fold enrichment (bootstrap 95% CI, 18.66-43.46). The complete 40-ancient-metabolite network connected all 6,798 associated F-groups into a single giant connected component (GCC). Even after stringent filtering, all 3,135 ancient-metabolite-associated F-groups remained in one GCC. Degree-preserving configuration-model randomizations and maximum-degree capping showed that this connectivity follows from the broad, recurrent distribution of metabolite binding rather than dependence on a few extreme hubs or a specialized higher-order topology. Differences between ancient and filtered non-ancient networks were not explained by metabolite size, whereas generic crystallization additives preferentially occupied smaller pockets. These results indicate that a limited ancient chemical repertoire established a globally connected protein- family architecture that subsequent metabolite diversification expanded while preserving its basic organization. SignificanceMetabolites are conventionally viewed as substrates, products, cofactors, or regulators acting on individual proteins. Global examination of experimentally observed metabolite-protein interactions reveals a broader organizing principle. Ancient metabolites combine local binding discrimination with extraordinary reuse across protein families, such that only 40 metabolites generate an almost completely connected network spanning thousands of ECOD (evolutionary classification of domains) protein families. The much larger non-ancient metabolite repertoire expands the protein-family space covered by this network, while preserving near-global connectivity. Thus, metabolite diversification appears to have elaborated, rather than created, a chemically connected protein architecture established early in evolution, suggesting that overlapping metabolite-binding repertoires could coordinate proteins, pathways, and cellular processes.

bioinformatics↗

bioRxiv2026

Protein-ligand binding kinetics are primarily controlled by the protein, not the ligand.

Protein-ligand interactions underpin biological regulation and drug action, with both binding affinity and binding kinetics shaping functional outcomes. By analysing kinetic data for 4,311 protein-small-molecule pairs, we find that when association occurs below the diffusion-controlled limit, the rates of ligand association (kon) and dissociation (koff) are primarily determined by how the initial encounter complex reorganizes into the final bound state, and that this reorganization is governed chiefly by the intrinsic dynamic properties of the protein rather than by structural features of the ligand. Counterintuitively, therefore, koff exhibits minimal dependence on ligand structure, so that dissociation proceeds through protein-gated conformational transitions rather than through direct rupture of protein-ligand contacts. This mechanistic behaviour stands in marked contrast to that for protein-protein complexes, based on an analysis of 1,561 interactions. Together, these findings challenge prevailing assumptions regarding the molecular determinants of small-molecule binding kinetics, and have broad implications for rationally modulating protein-ligand interactions and drug-target residence times.

biochemistry↗

bioRxiv2025

GlueFinder: A Data-Driven Framework for the Rational Discovery of Molecular Glues

Molecular glues can drive targeted protein degradation by stabilizing ternary complexes between proteins of interest and E3 ubiquitin ligases, but rational design has lagged due to limited rules for interface recognition and an overreliance on a few ligases (e.g., VHL or Cereblon). We introduce GlueFinder, a systematic, unbiased platform that leverages structural bioinformatics to mine the Protein Data Bank for ligand binding pockets adjacent to the protein interface which are ligandable sites near protein-protein interfaces that can nucleate glue-mediated complex formation. After validating its performance on a benchmark of experimentally solved dimeric structures with known and predicted glues, we applied GlueFinder to three therapeutically important targets, EGFR, HER2, and KRAS, and predicted candidate glues that recruit 24, 111, and 148 distinct E3 ligases to these targets, respectively. We further demonstrate that GlueFinder can promote the formation of non-native EGFR complexes, possibly enabling ternary assemblies that would not form on their own. Together, these results establish a general, computation-guided strategy for molecular glue discovery that decouples design from legacy degrader scaffolds and specific ligase dependencies, expands the usable E3 ligase repertoire, and enables rational targeting of interfacial binding pockets. GlueFinder thus broadens both the scope and precision of targeted protein degradation and moves the field toward mechanism-driven, systematic glue development across diverse therapeutic contexts. SignificanceMolecular glues are small molecules that destroy disease-causing proteins by helping them attach to cellular disposal machinery. However, current glue discovery depends on a few known ligases and lacks clear design rules. GlueFinder provides a general, computation-guided method that scans protein structures to find pockets near interfaces where glues can act. Applied to key targets such as EGFR, HER2, and KRAS, it predicts glues that connect many different ligases and even create new protein complexes. By revealing where and how glues can work, GlueFinder expands the range of degradable proteins and accelerates the rational design of future therapeutics.

bioinformatics↗

bioRxiv2023

Diet-induced miRNAs regulate adult neurogenesis and functional activity of nascent neurons in the hypothalamus

A high-fat diet (HFD) regulates the feeding circuitry in young-adult mice by stimulating neurogenesis from {beta}2 tanycytes in the hypothalamus. However, the fate of HFD-induced tanycytic neurogenesis, the functional attributes of the nascent neurons, and mechanisms underlying their subsequent integration into the feeding-related neural circuitry remain unclear. microRNAs (miRNAs) are known to play crucial roles in adult neurogenesis. In this study, miRNA profiling of BrdU-labelled neurogenic {beta}2 tanycytes from HFD-fed mice identified a cohort of miRNAs that originate from different chromosomal loci rather than a single genomic cluster. Network analysis of predicted targets for these HFD-induced miRNAs identified key "hub" mRNA targets that influence neurogenesis and the functional integration of newborn neurons. These HFD-induced miRNAs promoted the differentiation of nascent neurons into orexigenic AgRP+ and anorexigenic POMC+ neurons. Interestingly, only AgRP+ newborn neurons were selectively integrated into the functional feeding circuit, as detected by c-Fos immunostaining. This integration was disrupted when HFD-induced miRNA activity was suppressed via hypothalamic miRNA sponge expression. Furthermore, HFD feeding increased body weight in female mice, which was abrogated upon the inhibition of HFD-induced miRNAs. Magnetic resonance imaging (MRI) revealed elevated liver fat in HFD-fed mice, which reverted to normal levels when the HFD-induced miRNAs in hypothalamic tanycytes were blocked. Collectively, the findings from our study highlight a miRNA-mediated paradigm that links HFD-induced neurogenesis from {beta}2 tanycytes to weight gain and liver fat accumulation, and identifies the selective integration of AgRP+ neurons into the feeding circuitry as a possible causality of HFD-induced changes to body weight. Significance StatementThis study highlights a miRNA-network that biases the transcriptional program in hypothalamic tanycytes to promote neurogenesis in young adult mice following their exposure to an acute high-fat diet (HFD) paradigm. These HFD-induced miRNAs have the potential to alter the brains feeding circuitry by promoting neurogenesis and the preferential functional integration of nascent orexigenic (AgRP+) neurons; resulting in weight gain and hepatic fat accumulation. Collective inhibition of this miRNA-network prevents the integration of newborn AgRP+ neurons and reverses the metabolic consequences of high-fat diet. Our study provides an unexplored link between diet, neurogenesis, and remodeling of the feeding circuitry; and reveals potential therapeutic targets for combating hyperphagic obesity.

neuroscience↗

bioRxiv2023

Transcriptomic analysis identifies synapse-enriched lncRNAs required for glutamatergic synapse development and fear memory consolidation.

Regulatory functions of lncRNAs in neurons have been majorly limited to the nucleus. The identity of synaptic lncRNAs and their functional roles associated with synapse development and plasticity are poorly understood. Transcriptomic analysis from synaptoneurosomes identified 94 synapse-enriched lncRNAs from the mouse hippocampus. We find Pvt1 to be a specific regulator of excitatory, not inhibitory, synapse development. Synapse-specific loss of Pvt1 regulates synaptic activity and the downregulation of mRNAs pertinent to synapse development. We also report a synapse-centric role for an uncharacterized lncRNA; 2410006H16Rik (SynLAMP); in translation and memory formation. SynLAMP demonstrates enhanced localization to the synapse following fear conditioning and regulates dendritic translation by sequestering the translation repressor FUS; acting as a molecular decoy. Synapse-specific knockdown of SynLAMP inhibits the localised, activity-dependent translation of CamK2a, a FUS target. SynLAMP RNAi occludes fear-memory formation. Comprehensively, our study highlights that de novo activity of lncRNAs are involved in diverse synaptic functions.

neuroscience↗

bioRxiv2022

Fear extinction is regulated by long noncoding RNA activity at the synapse

Long noncoding RNAs (lncRNAs) represent a multidimensional class of regulatory molecules involved in many aspects of brain function. Emerging evidence indicates that lncRNAs are expressed at the synapse; however, a direct role for their activity in this subcellular compartment in memory formation has yet to be demonstrated. Using lncRNA capture-seq on synaptosomes, we identified a significant number of lncRNAs that accumulate at synapses within the infralimbic prefrontal cortex of adult male C57/Bl6 mice. Among these is a splice variant related to the stress-associated lncRNA, Gas5. RNA immunoprecipitation followed by mass spectrometry and single molecule imaging revealed that this Gas5 isoform, in association with the RNA binding proteins G3bp2 and Caprin1, regulates the activity-dependent trafficking and clustering of RNA granules in dendrites. In addition, we found that cell-type-specific, state-dependent, and synapse-specific knockdown of the Gas5 variant led to impaired fear extinction memory. These findings identify a new mechanism of fear extinction that involves the dynamic interaction between local lncRNA activity and the coordination of RNA condensates in the synaptic compartment.

neuroscience↗

bioRxiv2021

Enrichment of Zα domains at cytoplasmic stress granules is due to their innate ability to bind nucleic acids

Z domains are a subfamily of winged Helix-Turn-Helix (wHTH) domains found exclusively in proteins involved in the nucleic acids sensory pathway of vertebrate innate immune system and host evasion by viral pathogens. Interestingly, they are the only known protein domains that recognise the left-handed helical conformation of both dsDNA and dsRNA, known as Z-DNA and Z-RNA. Previously, it has been demonstrated that ADAR1 and ZBP1, two proteins possessing the Z domains, localize to cytosolic stress granules. It was further speculated that such localization is principally mediated by Z domains. To characterize and better understand such distinct and specific localization, we characterised the in vivo interactions and localization pattern for the amino terminal region of human DAI harbouring two Z domains (Z{beta}DAI). Using immunoprecipitation and mass spectrometry, we identified several interacting partners that were components of the complex formed by Z domains and RNAs. Differential interacting partners to wild-type Z, relative to mutant proteins, demonstrated that most of the physiologically relevant interactions are mediated by the nucleic acid binding ability of the Z{beta}. Further, we also show enrichment of selected complex components in cytoplasmic stress granules under conditions of stress. This ability is mostly lost in the mutants of Z{beta}DAI (Z{beta}DAI 4xmut) that lack nucleic-acid binding ability. Thus, we posit that the mechanism for the translocation of Z domain-containing proteins to stress granules is mainly mediated by the nucleic acid binding ability of their Z domains. Finally, we demonstrate that FUS and PSF/p54nrb, two RNA binding proteins with established roles in stress granules, interact with Z, which provides strong evidence for a role of these proteins in the innate immune system.

biochemistry↗

bioRxiv2020

Homeostatic scaling is driven by a translation-dependent degradation axis that recruits miRISC remodelling

Homeostatic scaling in neurons has been attributed to the individual contribution of either translation or degradation; however there remains limited insight towards understanding how the interplay between the two processes effectuates synaptic homeostasis. Here, we report that a co-dependence between protein synthesis and degradation mechanisms drives synaptic homeostasis whereas abrogation of either prevents it. Coordination between the two processes is achieved through the formation of a tripartite complex between translation regulators, the 26S proteasome and the miRNA-induced-silencing-complex (miRISC) components such as Argonaute, MOV10 and Trim32 on actively translating transcripts or polysomes. The components of this ternary complex directly interact with each other in an RNA-dependent manner. Disruption of polysomes abolishes this ternary interaction, suggesting that translating RNAs facilitate the combinatorial action of the proteasome and the translational apparatus. We identify that synaptic downscaling involves miRISC remodeling which entails the mTORC1-dependent translation of Trim32, an E3 ligase and the subsequent degradation of its target, MOV10 via the phosphorylation of p70 S6 kinase. We find that the E3 ligase Trim32 specifically polyubiquitinates MOV10 for its degradation during synaptic downscaling. MOV10 degradation alone is sufficient to invoke downscaling by enhancing Arc translation through its 3 UTR and causing the subsequent removal of post-synaptic AMPA receptors. Synaptic scaling was occluded when we depleted Trim32 and overexpressed MOV10 in neurons, suggesting that the Trim32-MOV10 axis is necessary for synaptic downscaling. We propose a mechanism that exploits a translation-driven protein degradation paradigm to invoke miRISC remodeling and induce homeostatic scaling during chronic network activity.

neuroscience↗

bioRxiv2018

Continued circulation, recombination and evolution of the ancient subcontinent lineage despite predominance of the recent arctic-like lineage rabies viruses (RABV) in India

BackgroundRabies is an emerging and re-emerging lethal encephalitis causing 26,400 to 61,000 human deaths annually. Approximately 20,000 people die of rabies every year in India that accounts to 36% of the worlds rabies deaths. Rabies is endemic among domestic dogs in India and there are conflicting reports on the currently circulating RABV lineages in domestic dogs in India. Further, movement of humans and animals between Sri Lanka and southern coastal states of India was proposed to be a source of the emergence of variant RABV in India. For effective prevention and control of rabies in India it is essential to establish the genetic diversity and evolutionary dynamics of RBAV currently circulating in India.\n\nMethodsWe carried out molecular evolution and recombination analyses of nucleoprotein (N) and glycoprotein (G) genes of 26 RABV isolates from southern Indian states of Tamil Nadu and Goa.\n\nResultsWe found continued co-circulation of ancient subcontinent lineage despite predominance of the recent arctic-like lineage RABVs in southern India. The mean rate of nucleotide substitution in G and N genes was 1.32 x 10-3 and 1.91 x 10-4 substitutions/site/yr respectively. The study also found recombination in both N and G genes and a higher mean rate of evolutionary changes in G gene among Indian dog RABV isolates than those of lyssaviruses. The Indian subcontinent lineage RABV isolates investigated in this study clustered closely with other subcontinent lineage viruses from Sri Lanka highlighting the continued incursion and/or circulation of the variant subcontinent lineages of RABVs between India and Sri Lanka.\n\nConclusionWe report that there is enzootic viral establishment of two distinct RABV lineages in domestic dogs in India that are evolving at a greater rate.\n\nAuthor summaryRabies is a fatal viral disease that has no treatment and can only be prevented by post-exposure vaccination. In many parts of Asia and Africa, rabies continues to be a major public health threat almost always caused by dog bites. In this study, we investigated the genetic diversity and rate of evolution among rabies viruses isolated from dogs in India. We found that two distinct lineages of Rabies viruses (RABVs) namely the ancient subcontinent lineage and a more recent arctic-like lineage co-circulate among dogs in India. Notably, our study found that the dog rabies viruses in India are undergoing recombination and evolving at a higher rate than other lyssaviruses. Phylogenetic analysis revealed continued incursion and/or circulation of the variant subcontinent lineages of RABVs in India that might have been originated from Sri Lanka. Our study indicates that two distinct lineages of RABVs are maintained and currently circulate among dog population in India

microbiology↗