Kinase-substrate prediction using an autoregressive model

Computational and Structural Biotechnology Journal, Journal Year: 2025, Volume and Issue: 27, P. 1103 - 1111

Published: Jan. 1, 2025

Kinase-specific phosphorylation plays a critical role in cellular signaling and various diseases. However, even model organisms, the substrates of most kinases remain unidentified. Currently, there is no reliable method to predict kinase-substrate relationships. In this study, we introduce an innovative approach leveraging autoregressive pairs. Unlike traditional methods focused on predicting site-specific phosphorylation, our addresses kinase-specific protein substrate prediction at level. We redefine problem as special type protein-protein interaction task. Our integrates large language ESM-2 encoder employs decoder classify protein-kinase interactions binary fashion. adopted hard negative strategy, based kinase embedding distances generated from ESM-2, compel effectively distinguish positive data. conducted top‑k analysis assess how well can prioritize likely candidates. also capable zero-shot prediction, meaning it for case known substrates, which cannot be achieved by methods. model's robust generalization novel underrepresented groups showcases its versatility broad utility. Code data are available https://github.com/farz1995/substrate_kinase_prediction.

Language: Английский

Targeting senescence in Amyotrophic Lateral Sclerosis: senolytic treatment improves neuromuscular function and preserves cortical excitability in a TDP-43Q331K mouse model.

Research Square (Research Square), Journal Year: 2025, Volume and Issue: unknown

Published: March 26, 2025

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder marked by progressive motor neuron degeneration in the primary cortex (PMC) and spinal cord. Aging key factor ALS onset progression, with evidence suggesting that biological aging-a process involving cellular decline- far outpaces chronological aging ALS. This promotes senescent cell accumulation-marked irreversible cell-cycle arrest, impaired apoptosis, chronic inflammation-disrupting tissue homeostasis impairing neuronal support functions. Thus, targeting senescence presents novel therapeutic strategy for Here, we investigated senolytic combination Dasatinib Quercetin (D&Q) TDP-43 Q331K mice. D&Q improved neuromuscular function reduced plasma neurofilament light chain, biomarker of axonal damage. The most pronounced improvement was cortical excitability, accompanied reductions PMC. These findings highlight potential senolytics to mitigate ALS-related dysfunction, supporting their viability as strategy. *Jose A. Viteriab, Nathan R. Kerrab, Charles D. Brennana are co-first authors.

Language: Английский