Biology subjects

Irshad, M.

Publications and source records attributed to Irshad, M..

5 recordsLinked to original sources

bioRxiv2026

Probing Mechanisms of Allosteric Regulation in AAA+ ATPases for Microtubule Severing and Protein Disaggregation

Ring-like AAA+ (ATPases Associated with diverse cellular Activities) biological machines mediate protein remodeling to assist a broad range of essential cellular functions. The nucleotide-dependent remodeling action involves intra- and inter-ring allosteric communication to generate mechanical force applied onto the substrate by a set of loops that protrude into the central channel. In this study, we probe these allosteric mechanisms through a comparative study of the katanin, a microtubule severing protein including a clade 3 AAA domain, and the double-ring ClpB, a protein disaggregase including both a clade 3 and a clade 5 AAA domain. Our molecular dynamics simulations, combined with machine learning and bioinformatic analysis, reveal both similar mechanisms involving the clade 3 domain and ClpB-specific ones involving communication with the clade 5 domain. We find that both nucleotide and substrate polypeptide binding restrict the conformational landscape sampled by katanin and ClpB, with ligand-specific conformations observed in the latter case. Allosteric contributions of secondary structure elements, ranked by using SHapley Additive exPlanations analysis in machine learning approaches and binary classification of features in ligand states, highlight the important role of regions adjacent to the nucleotide-binding site and the pore loops. Amino acid-level analysis of the allosteric paths reveals that intra-ring cooperativity modulates long-distance communication within the AAA+ protomers.

biophysics↗

bioRxiv2026

FlexENN: A Graph Neural Network for Binding Energy Prediction of Globular and Intrinsically Disordered Proteins

Intrinsically disordered proteins (IDPs) drive a large fraction of cellular signaling, transcription and assembly through interfaces that lack a single defined geometry, making the prediction of their binding energies beyond the reach of methods calibrated on the rigid complementarity of folded complexes. Here we introduce an adaptive message passing graph neural network, FlexENN, that predicts binding energies across the full structural spectrum, from folded domains to complexes with one disordered partner. The FlexENN architecture constructs a local interface graph in which each residue node integrates relative geometry, dynamic descriptors, and sequence information, allowing the network to infer conformational fuzziness from a single structure. Benchmarked across folded complexes and IDP systems, including tubulin-tubulin interfaces within microtubules (MTs) and MTs in complex with microtubule associated proteins (MAPs), with reference binding affinity values extracted from our experiments, the model retrieves physically meaningful energetic profiles for complexes where rigid-body methods fail. More broadly, this work delivers an accurate, structure-aware approach to predicting binding free energies for the broad class of disordered-mediated complexes formed by IDPs.

biophysics↗

bioRxiv2024

Widespread Neuroanatomical Integration and Distinct Electrophysiological Properties of Glioma-Innervating Neurons

Gliomas are the most common malignant primary brain tumors and are often associated with severe neurological deficits and mortality. Unlike many cancers, gliomas rarely metastasize outside the brain, indicating a possible dependency on unique features of brain microenvironment. Synapses between neurons and glioma cells exist, suggesting that glioma cells rely on neuronal inputs and synaptic signaling for proliferation. Yet, the locations and properties of neurons that innervate gliomas have remained elusive. In this study, we utilized transsynaptic tracing with a pseudotyped, glycoprotein-deleted rabies virus to specifically infect TVA and glycoprotein-expressing human glioblastoma cells in an orthotopic xenograft mouse model, allowing us to identify the neurons that form synapses onto the gliomas. Comprehensive whole-brain mapping revealed that these glioma-innervating neurons (GINs) consistently arise at brain regions, including diverse neuromodulatory centers and specific cortical layers, known to project to the glioma locations. Molecular profiling revealed that these long-range cortical GINs are predominantly glutamatergic, and subsets express both glutamatergic and GABAergic markers, whereas local striatal GINs are largely GABAergic. Electrophysiological studies demonstrated that while GINs share passive intrinsic properties with cortex-innervating neurons, their action potential waveforms are altered. Our study introduces a novel method for identifying and mapping GINs and reveals their consistent integration into existing location-dependent neuronal network involving diverse neurotransmitters and neuromodulators. The observed intrinsic electrophysiological differences in GINs lay the groundwork for future investigations into how these alterations may correspond with the postsynaptic characteristics of glioma cells. SignificanceWe have developed a novel system utilizing rabies virus-based monosynaptic tracing to directly visualize neurons that synapse onto human glioma cells implanted in mouse brain. This approach enables the mapping and quantitative analysis of these glioma-innervating neurons (GINs) in the entire mouse brain and overcomes previous barriers of molecular and electrophysiological analysis of these neurons due to the inability to identify them. Our findings indicate that GINs integrate into existing neural networks in a location-specific manner. Long-range GINs are mostly glutamatergic, with a subset expressing both glutamatergic and GABAergic markers and local striatal GINs are GABAergic, highlighting a complex neuromodulatory profile. Additionally, GINs exhibit unique action potential characteristics, distinct from similarly selected neurons in non-tumor-bearing brains. This study provides new insights into neuronal adaptations in response to forming putative synapses onto glioma, elucidating the intricate synaptic relationship between GINs and gliomas.

cancer biology↗

bioRxiv2020

Apical-root apoplastic acidification affects cell-wall extensibility in wheat under salinity stress

Plant salt tolerance is closely associated with a high rate of root growth. Although root growth is governed by cell-wall and apoplastic pH, the relationship between these factors in the root elongation zone under salinity stress remains unclear. Here, we assess apoplastic pH, pH- and expansin-dependent cell-wall extensibility, and expansin expression in the root elongation zone of salt-sensitive (Yongliang-15) and -tolerant (JS-7) cultivars under salinity stress. A six-day 80 mM NaCl treatment significantly reduced apical-root apoplastic pH, from 6.2 to 5.3, in both cultivars. Using a pH-dependent cell-wall extensibility experiment, we found that, under 0 mM NaCl treatment, the optimal pH for cell-wall loosening was 6.0 in the salinity-tolerant cultivar and 4.6 in the salinity-sensitive cultivar. Under 80 mM treatment, a pH of 5.0 mitigated the cell-wall stiffness caused by salinity stress in the salinity-tolerant cultivar, but promoted cell-wall stiffening in the salinity-sensitive cultivar. These changes in pH-dependent cell-wall extensibility are consistent with differences in the root growth of two cultivars under salinity stress. Exogenous expansin application, and expansin expression experiments, we found that salinity stress altered expansin expression, differentially affecting cell-wall extensibility under pH 5.0 and 6.0. TaEXPA7 and TaEXPA8 induced cell-wall loosening at pH 5.0, whereas TaEXPA5 induced cell-wall loosening at pH 6.0. These results elucidate the relationship between expansin and cell-wall extensibility in the root elongation zone, with important implications for enhancing plant growth under salinity stress.

plant biology↗

bioRxiv2019

Phytohormonal cross-talk modulate Bipolaris sorokiniana (Scc.)interaction with Zea mays

Besides acting as growth inducing molecule, Gibberellin (GA3) also confers the compatibility of microbial interactions with host. We inoculated 11 days old Z. mays seedlings grown under hydroponic conditions and high GA3 levels with Bipolaris sorokiniana (BIPOL) at the spore density (SD) of OD0.6. The high level of GA3 negatively affected the growth of the seedlings, accompanied by the high level of stress deducing secondary metabolites (proline, total flavanoids, phenylpropanoids, and glucosinolides). Moreover, high level of GA3 produced a hypersensitive response (HR) in the seedlings. The HR developed cross talks with IAA and trans-zeatins and triggered higher production of hypersensitive inducing biomolecules. The other HR co-related biological processes were demonstrated by high phytoalexins level and high protease activities. Such activities ultimately inhibited the colonization of BIPOL on the roots of maize seedlings. The products of the genes expressed at high GA3 also conferred the deterrence of BIPOL colonization at SD = OD0.6. Intriguingly, when we inhibited GA3 biosynthesis in the seedlings with aerially sprayed uniconizole, prior to BIPOL treatment, the BIPOL colonized and subsequently promoted the seedling growth. This low level of GA3 after BIPOL treatment checked the high level of secondary metabolites and hypersensitivity inducing molecules. The results, thus suggested that the aforementioned processes only happened in the BIPOL at SD (OD0.6), whereas the SD at lower levels (OD0.2 or OD0.4) neither promoted the growth of uniconizole pre-treated seedlings nor produced HR in control seedlings of maize plant.

physiology↗