Biology subjects

Syrris, P.

Publications and source records attributed to Syrris, P..

3 recordsLinked to original sources

bioRxiv2026

Cysteine Glutathionylation as a Global Dynamic Regulator of Protein Active Site Accessibility and Protein Complex Formation

Protein-glutathionylation is traditionally viewed as a protective mechanism that shields cysteine-residues from irreversible oxidative damage. Its broader functional roles remain poorly understood, in part due to technical limitations in detecting this modification at scale. Here, we develop and leverage a new mass-spectrometry approach that preserves protein-glutathionylation, thereby revealing its widespread distribution across the proteome in cell models, worms, mice and human cardiac tissues. In all cases, we find that glutathionylation sites are enriched at both protein-protein interfaces and protein-active sites, and are highly conserved across species. We find that glutathionylation is dynamically redistributed in response to environmental challenges, thereby driving remodelling of cellular protein-protein interaction (PPI) networks, and access to protein active sites, with functional and phenotypic consequences. Finally, we show that glutathionylation accumulates on key cardiac-sarcomeric proteins in aged-mice and human cardiomyopathy biopsies, revealing its role in cardiovascular dysfunction. These findings reposition glutathionylation as a crucial regulatory PTM, akin to phosphorylation, that orchestrates adaptive cellular responses. This work redefines the role of glutathionylation, with broad implications for cell biology and disease.

molecular biology↗

bioRxiv2023

Unlocking Predictive Power: A Machine Learning Tool Derived from In-Depth Analysis to Forecast the Impact of Missense Variants in Human Filamin C

Cardiomyopathies, diseases of the heart muscle, are a leading cause of heart failure. An increasing proportion of cardiomyopathies have been associated with specific genetic changes, such as mutations in FLNC, the gene that codes for filamin C. Altogether, more than 300 variants of FLNC have been identified in patients, including a number of single point mutations. However, the role of a significant number of these mutations remains unknown. Here, we conducted a comprehensive analysis, starting from clinical data that led to identification of new pathogenic and non-pathogenic FLNC variants. We selected some of these variants for further characterization that included studies of in vivo effects on the morphology of neonatal cardiomyocytes to establish links to phenotype, and the in vitro thermal stability and structure determination to understand biophysical factors impacting function. We used these findings to compile vast datasets of pathogenic and non-pathogenic variant structures and developed a machine-learning-based neural network (AMIVA-F) to predict the impact of single point mutations. AMIVA-F outperformed most commonly used predictors both in disease related as well as neutral variants, approaching [~]80% accuracy. Taken together, our study documents additional FLNC variants, their biophysical and structural properties, and their link to the disease phenotype. Furthermore, we developed a state-of-the-art web-based server AMIVA-F that can be used for accurate predictions regarding the effect of single point mutations in human filamin C, with broad implications for basic and clinical research.

biophysics↗

bioRxiv2022

Alpha kinase 3 signaling at the M-band maintains sarcomere integrity and proteostasis in striated muscle.

Pathogenic variants in alpha kinase 3 (ALPK3) cause cardiomyopathy and musculoskeletal disease. How ALPK3 mutations result in disease remains unclear because little is known about this atypical kinase. Using a suite of engineered human pluripotent stem cells (hPSCs) we show that ALPK3 localizes to the M-Band of the sarcomere. ALPK3 deficiency disrupted sarcomeric organization and calcium kinetics in hPSC-derived cardiomyocytes and reduced force generation in cardiac organoids. Phosphoproteomic profiling identified ALPK3-dependant phospho-peptides that were enriched for sarcomeric components of the M-band and the ubiquitin-binding protein SQSTM1. Analysis of the ALPK3 interactome confirmed binding to M-band proteins including SQSTM1. Importantly, in hPSC-derived cardiomyocytes modeling ALPK3 deficiency and cardiomyopathic ALPK3 mutations, sarcomeric organization and M-band localization ofSQSTM1 were abnormal. These data suggest ALPK3 has an integral role in maintaining sarcomere integrity and proteostasis in striated muscle. We propose this mechanism may underly disease pathogenesis in patients with ALPK3 variants.

cell biology↗