Biology subjects

Schahl, A.

Publications and source records attributed to Schahl, A..

5 recordsLinked to original sources

bioRxiv2025

Ancestral neuronal receptors are bacterial accessory toxins

Symbiosis and horizontal gene transfer events were crucial in the emergence of eukaryotic and multicellular life. A striking example is the acquisition of Teneurins, putative surface-exposed toxins in bacteria that function as cell adhesion receptors in metazoan neuronal development. Here, we demonstrate the evolutionary relationships between metazoan and bacterial Teneurins. We show that bacterial Teneurins are accessory proteins, that harbour diverse encapsulated toxins. They predominate in species with complex social behaviours, suggesting roles in both cell-to-cell competition and cooperation. Metazoan Teneurins are therefore repurposed bacterial toxins central to cell-to-cell communication in nervous systems. Their acquisition was a foundational event in the evolution of metazoans.

biochemistry↗

bioRxiv2025

Lipid-facilitated opening of the ADAM10 sheddase revealed by enhanced sampling simulations

ADAM10 is a crucial membrane-bound metalloprotease that regulates cellular physiology by cleaving and releasing membrane-anchored proteins, including adhesion molecules and growth factor precursors, thereby modulating cell signaling, adhesion, and migration. Despite its central role, its activation mechanisms are not fully understood. Here, we model how phosphatidylserine (PS) exposure during apoptosis triggers ADAM10 activation. We confirmed that PS externalization leads to shedding of CD43 from the surface of T cells via ADAM10 activity. Intriguingly, ADAM10 activation correlated with a loss of monoclonal ADAM10 antibody binding, suggesting a PS-induced conformational change that alters epitope accessibility. To explore this lipid-mediated conformational change of ADAM10, we employed molecular dynamics (MD) simulations to map the conformational landscape of ADAM10. Our simulations revealed that in the absence of PS, ADAM10 samples predominantly closed and intermediate states. By contrast, the presence of PS destabilizes the closed conformation, thereby favoring open states. We provide a mechanistic explanation for this PS-induced conformational change which drives ADAM10 activation and loss of mAb binding through conformational change. These findings offer new insights into the lipid-mediated regulation of ADAM10 and its conformational dynamics.

biophysics↗

bioRxiv2025

Structure of the central Staphylococcus aureus AAA+ protease MecA/ClpC/ClpP

Bacterial AAA+ proteases are composed of a AAA+ partner (e.g. ClpC) and an associated peptidase (e.g. ClpP). They represent ATP-fuelled and self-compartmentalized proteolytic machines that are crucial for stress resistance and virulence. ClpC requires cooperation with adaptor proteins such as MecA for activation and complex formation with ClpP. Here, we present the cryo-EM structure of the MecA/ClpC/ClpP complex from the major pathogen Staphylococcus aureus. MecA forms a dynamic crown on top of the ClpC/ClpP complex with its substrate-binding domain positioned near the ClpC pore site, likely facilitating substrate transfer. ClpC/ClpP complex formation involves ClpC P-loops and ClpP N-terminal {beta}-hairpins, which insert into the central ClpC threading channel and contact sites next to the ClpC ATPase center. ClpC and ClpP interactions are asymmetric and dictated by the activity states of ClpC ATPase subunits. ClpP binding increases ClpC ATPase and threading activities in a {beta}-hairpin dependent manner, illuminating an allosteric pathway in the cooperation of ATPase and peptidase components in bacterial AAA+ proteases.

biochemistry↗

bioRxiv2022

????-actin plasticity is modulated by coordinated actions of histidine 73 methylation, nucleotide type, and ions

The functional importance of the methylation of histidine 73 (H73) in actin remains unclear. Focusing on cytoplasmic {beta}-actin, present in all mammalian cells, we use molecular dynamics simulations with a polarizable force field and adaptive sampling to examine the effects of H73 methylation. Our results show that methylation enhances nucleotide binding cleft opening, alters allosteric pathways connecting subdomains 2 and 4 (SD2 and SD4) in G-actin, and affects backdoor openings and inorganic phosphate release in F-actin, as validated by biochemical assays. These effects depend on the nucleotide and ions interacting with the actin. Together, our findings reveal how H73 methylation regulates {beta}-actin plasticity and integrates environmental cues.

biophysics↗

bioRxiv2021

Interactome analyses reveal profound proteasome structural and functional rearrangements throughout mammalian spermatogenesis

During spermatogenesis, spermatogonia undergo a series of mitotic and meiotic divisions on their path to spermatozoa. To achieve this, a succession of processes requiring high proteolytic activity are in part orchestrated by the proteasome. The spermatoproteasome (s20S) is specific to the developing gametes, in which the gamete-specific 4s subunit replaces the 4 isoform found in the constitutive proteasome (c20S). Although the s20S is conserved across species and was shown to be crucial for germ cell development, its mechanism, function and structure remain incompletely characterized. Here, we used advanced mass spectrometry (MS) methods to map the composition of proteasome complexes and their interactomes throughout spermatogenesis. We observed that the s20S becomes highly activated as germ cells enter meiosis, mainly through a particularly extensive 19S activation and, to a lesser extent, PA200 binding. Additionally, the proteasome population shifts from c20S (98%) to s20S (>82-92%) during differentiation, presumably due to the shift from 4 to 4s expression. We demonstrated that s20S, but not c20S, interacts with components of the meiotic synaptonemal complex, where it may localize via association with the PI31 adaptor protein. In vitro, s20S preferentially binds to 19S, and displays higher trypsin- and chymotrypsin-like activities, both with and without PA200 activation. Moreover, using MS methods to monitor protein dynamics, we identified significant differences in domain flexibility between 4 and 4s. We propose that these differences induced by 4s incorporation result in significant changes in the way the s20S interacts with its partners, and dictate its role in germ cell differentiation.

biochemistry↗