Biology subjects

Quinlan, J.

Publications and source records attributed to Quinlan, J..

3 recordsLinked to original sources

bioRxiv2026

MICAL-Inspired Chiral Vanadate Nanoclusters Decelerate Actin Dynamics in Live Cells

Actin turnover is a fundamental cellular process essential for cell dynamics, whose control is critical for both medicine and biotechnology. However, conventional small molecules modifying actin turnover scramble the structure of actin filaments and display high cellular toxicity. MICAL enzymes oxidizing methionine (Met) residues in actin can potentially address this challenge, but their large size and multiple required cofactors make MICALs manufacturing and utilization difficult. Here we show that redox-active chiral decavanadate nanoclusters with tartaric acid are capable of site-selective actin modulation, mimicking MICALs, while requiring no cofactors, displaying high biocompatibility and being membrane permeable. Decavanadate nanoclusters serve as atomically precise "nano-enzymes" oxidizing three Met residues in globular actin, including Met-176; the latter inhibits the opening of the backdoor segment and prevents depolymerization of actin filaments. The structure of actin filaments formed after nanocluster treatment revealed no structural disturbances as confirmed by cryo-electron microscopy. The biocompatibility and bioactivity of chiral decavanadate nanoclusters was demonstrated by modulation of actin in living NG108-15 cells. Taking advantage of atomically precise structure of the nanoclusters, we show that their docking into actin can be predicted computationally, indicating the possibility of programmable actin modulation using the tools of nanochemistry.

biochemistry↗

bioRxiv2025

Biophysical Modeling Elucidates Mechanistic Principles for Rational Molecular Glue Design

Molecular glues are small molecules that offer a powerful strategy to target previously "undruggable" proteins of interest (POI) by enhancing their interactions with other proteins (effector). Depending on the nature of the effectors, molecular glues can induce stabilizing sequestration or degradation of POI. However, their rational design has been hindered by a poor understanding of how kinetic parameters impact their performance. To address this, we developed a unified mathematical framework that accurately analyzes the dynamics of both glue degraders and stabilizers. Our model reveals that the strong binding affinity of the ternary complex is the key determinant of performance across both modalities, provided that the initial component concentrations and degradation rate constants are fixed. Furthermore, we demonstrate that degrader performance is ultimately limited by its catalytic efficiency and the target proteins natural half-life. We also identify distinct roles for effector abundance, showing that the relative concentrations of the effector and POI are critical for stabilizers but less so for degraders. This quantitative framework provides mechanistic principles for the rationale design and optimization of molecular glues.

molecular biology↗

bioRxiv2023

Inflammation induces bitter taste oversensitization via epigenetic changes in Tas2r gene clusters

T2R bitter receptors, encoded by Tas2r genes, are not only critical for bitter taste signal transduction but also important for defense against bacteria and parasites. However, little is known about whether and how Tas2r gene expression are regulated. Here we show that, in an inflammation model mimicking bacterial infection, the expression of many Tas2rs are significantly up-regulated and mice displayed markedly increased neural and behavioral responses to bitter compounds. Using single-cell assays for transposase-accessible chromatin with sequencing (scATAC-seq), we found that the chromatin accessibility of Tas2rs was highly cell type specific and inflammation increased the accessibility of many Tas2rs. scATAC-seq also revealed substantial chromatin remodeling in immune response genes in taste tissue stem cells, suggesting potential long-term effects. Together, our results suggest an epigenetic mechanism connecting inflammation, Tas2r gene regulation, and altered bitter taste, which may explain heightened bitter taste that can occur with infections and cancer treatments.

neuroscience↗