Biology subjects

Chavali, S.

Publications and source records attributed to Chavali, S..

8 recordsLinked to original sources

bioRxiv2026

Amino acid repeat mosaics shape protein functional landscape

How combinations of functional units such as repeats and motifs within disordered regions influence protein functions remains poorly understood. Here, we investigate how co-occurring amino acid homorepeats of different types within the same protein (HR-mosaics) shape molecular outcomes. Using a novel evolutionary co-occurrence metric, human HR-mosaics were classified as segregated (each HR independently influences distinct outcomes), concerted-disjunct (both HRs jointly shape protein functionality without modulating each other), or concerted-conjunct (both HRs affect functionality through mutual influence). Molecular studies of naturally occurring polyGly-polyPro mosaic in DDX17 and chimeric mosaics of polyAla and polyHis demonstrate that HR-mosaics influence protein abundance, localisation, mobility and interaction landscape. Segregated HR-mosaics expand functional space, concerted-disjunct additionally confer biological context, and concerted-conjunct mosaics further enable rheostatic regulation between HRs. These design principles underscore amino acid type, length and relative positioning of HRs as central architects of HR-mosaic functionality, with implications in protein design and engineering and understanding repeat-associated pathologies.

Systems Biology↗

bioRxiv2026

Transcription termination safeguards quiescent chromatin for faithful cell-cycle re-entry

Quiescence is a conserved program of endurance and readiness in non-cycling cells that is fundamental to the longevity of eukaryotic lineages, from clonal microbial populations to human regenerative tissues. While this G0 state is universally associated with a compact chromatin organization, the active safeguards that preserve this structural template--and their necessity for future division competence and fidelity--remain unknown. Here we show, using fission yeast as a model, that chromatin structural maintenance in quiescence requires the enforcement of transcription termination by the conserved factor Ppn1PNUTS/Ref2. We identify a minimal disordered region in Ppn1 that resolves a physical conflict in the quiescent genome by preventing the transcriptional "eviction" of cohesin. Loss of this safeguard drives a progressive structural erosion that deregulates cyclin-dependent kinase (CDK) dynamics and causes lethal aneuploidy upon cell-cycle re-entry. Notably, this deterioration is not an inevitable terminal state; re-establishing termination via a brief Ppn1 pulse resets division fidelity by stabilizing a core de novo cohesin landscape. These findings redefine quiescent chromatin as an actively maintainable blueprint rather than a passive standby state established at G0 entry. We propose that "quiescence exhaustion" is driven by transcriptional stress eroding genomic organization, defining a structural limit to cellular longevity.

genetics↗

bioRxiv2025

Molecular attributes of intrinsically disordered regions in secretomes influence fungal pathogenesis

Secretory proteins are crucial for establishing fungal infection through biomolecular interactions with the host. Accumulating evidence suggest that intrinsically disordered regions (IDRs) in proteins facilitate molecular interactions. How do IDRs of secretory proteins influence fungal pathogenesis? By analyzing 195,359 secretory proteins of 73 fungal species, we find that IDRs in plant pathogen extracellular non-effectors are enriched for weak polyampholytes and polyelectrolytes. These could adopt beads-on-string conformation effectively promoting assembly of diverse enzymes aiding swift degradation of host cell wall. Both animal pathogen secretory proteins and intracellular plant pathogen effectors show enrichment for strong polyampholytes, potentially aiding phase-separation and organizing intracellular biological matter to hijack or suppress host machinery. Importantly, IDRs of plant pathogen effectors which mimic host IDRs could have emerged through convergent evolution, while those of non-effectors might have evolved de novo. Thus, specific molecular attributes of fungal secretome IDRs can influence initiation, establishment and long-term persistence of infection.

systems biology↗

bioRxiv2025

ERF transcription factor regulons underpin growth-defence trade-off under acute heat stress in rice seedlings

O_LIRice, a staple cereal crop, faces significant threats from rising temperatures, affecting all growth stages including early seedling establishment. Despite being critical in determining overall growth and productivity, response to heat stress during the early seedling stage remains understudied. This research aimed to assess the impact of acute heat stress on rice seedlings and unravel underlying molecular mechanisms. C_LIO_LIRice seedlings were exposed to varying intensities and durations of heat stress to determine a critical threshold affecting growth. To elucidate the transcription factor (TF)-mediated regulatory mechanisms and their functional interactome in response to stress, transcriptomic analysis of shoots and roots exposed to acute heat stress was performed. C_LIO_LITranscriptome analysis unveiled a comprehensive TF-target regulatory map for shoots and roots, potentially involved in the modulation of growth-defence trade-off in response to acute heat stress. Ethylene Responsive Factors (ERFs) emerged as central regulators, with phytohormones ethylene and jasmonic acid acting as upstream modulators. Pre-treatment with these phytohormones alleviated the adverse effects of heat stress. C_LIO_LIThis study uncovers key molecular mechanisms governing rice seedling responses to acute heat stress involving ERFs-hormonal interactions. Modulating these core regulators presents a promising strategy to enhance heat resilience, addressing global food security amid rising temperatures. C_LI

plant biology↗

bioRxiv2025

Amino acid repeat signatures underlying human-pathogen interactions

Emerging evidence suggests that amino acid homorepeats (HRs) in proteins (HRPs) contribute to protein interactability. What is the role of HRs in human-pathogen protein interactions? We find that pathogens engage physiologically important human HRPs, thereby affecting diverse host physiological processes. From the pathogen standpoint, (i) eukaryotic pathogens engage more HRPs but with host-sparse HRs, leading to disparate and discriminate interactions, (ii) prokaryotic pathogens engage less HRPs but with host-abundant non-polar HRs via host protein proxies bringing about discriminate or promiscuous interactions and (iii) viral pathogens engage more HRPs with host-abundant polar uncharged HRs affecting promiscuous interactions using host-partner HR tract mimicry. To propel further research, we introduce a resource Hi-PHI (http://hiphi.iisertirupati.ac.in/) cataloging critical information about human and pathogen HRPs and HRs. We propose mechanisms to (i) repurpose drugs targeting human HRPs engaged by pathogens for treating different infections and (ii) exploit HRs and their flanks as targets for pathogen-targeted anti-infectives.

systems biology↗

bioRxiv2024

RNA binding protein Musashi1 interacts with the viral genomic RNA and restricts SARS-CoV-2 infection by repressing translation

Musashi RNA binding proteins are important post-transcriptional regulators of stem cell homeostasis and are known to be involved in viral infections. However, their role in SARS-CoV-2 infection remains largely unknown. Using computational studies, in vivo RNA immunoprecipitation and biochemical assays, here, we establish that Musashi1 (Msi1) interacts with viral genomic RNA through direct binding to the SARS-CoV-2 3UTR. Importantly, binding of Msi1 to the viral 3UTR results in translational repression mediated by inhibition of Poly (A) binding protein (PABP). Conversely, Msi1 knockout promotes robust viral replication and increased viral protein expression. Using 2D cell cultures, stem cells and 3D organoids, we show that depletion of Msi1 in intestinal cells augments infection. This finding explains why the human intestine serves as a reservoir for the SARS-CoV-2 virus, wherein differentiated enterocytes, which have negligible levels of Msi1, are highly affected. Contrarily, stem cells which are enriched for Msi1 expression, are known to be less permissive to SARS-CoV-2 infection despite expressing the entry receptors. Our findings show how translation repression of SARS-CoV-2 by stem cell RNA binding proteins such as Msi1 could help evasion of infection.

cell biology↗

bioRxiv2022

Proteins with amino acid repeats constitute rapidly evolvable and human-specific essentialome

Protein products of essential genes, indispensable for organismal survival, are highly conserved and bring about fundamental functions. Interestingly, proteins that contain amino acid homorepeats that tend to evolve rapidly are enriched in eukaryotic essentialomes. Why are proteins with hypermutable homorepeats enriched in conserved and functionally vital essential proteins? We solve this function versus evolutionary paradox by demonstrating that human essential proteins with homorepeats bring about cross-talk across biological processes through high interactability and have distinct regulatory functions affecting expansive global regulation. Importantly, essential proteins with homorepeats rapidly diverge with the amino acid substitutions frequently affecting functional sites, likely facilitating rapid adaptability. Strikingly, essential proteins with homorepeats influence human-specific embryonic and brain development, implying that the presence of homorepeats could contribute to the emergence of human-specific processes. Thus, we propose that homorepeat containing essential proteins affecting species-specific traits can be potential intervention targets across pathologies including cancers and neurological disorders.

systems biology↗

bioRxiv2018

Heteromeric GABAA receptor structures in positively-modulated active states

Type-A {gamma}-aminobutyric acid (GABAA) receptors are pentameric ligand-gated ion channels (pLGICs), typically consisting of /{beta}/{gamma} subunit combinations. They are the principal mediators of inhibitory neurotransmission throughout the central nervous system and targets of major clinical drugs, such as benzodiazepines (BZDs) used to treat epilepsy, insomnia, anxiety, panic disorder and muscle spasm. However, the structures of heteromeric receptors and the molecular basis of BZD operation remain unknown. Here we report the cryo-EM structure of a human 1{beta}3{gamma}2 GABAAR in complex with GABA and a nanobody that acts as a novel positive allosteric modulator (PAM). The receptor subunits assume a unified quaternary activated conformation around an open pore. We also present crystal structures of engineered 5 and 5{gamma}2 GABAAR constructs, revealing the interfacial site for allosteric modulation by BZDs, including the binding modes and the conformational impact of the potent anxiolytic and partial PAM, bretazenil, and the BZD antagonist, flumazenil. These findings provide the foundation for understanding the mechanistic basis of GABAAR activation.

biophysics↗