Lipid‐Facilitated Opening of the ADAM10 Sheddase Revealed by Enhanced Sampling Simulations
Year: 2026
Type: article
Abstract: 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 confirm that PS externalization is associated with ADAM10-mediated CD43 shedding from the surface of T cells. Intriguingly, ADAM10 activation correlated with loss of ADAM10 monoclonal 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 simulations to map its conformational landscape. 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.
Source: Advanced Science
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,730
Funders: Hevolution Foundation, European High Performance Computing Joint Undertaking, Human Frontier Science Program, UK Research and Innovation, University of Oxford, Karolinska Institutet, Knut och Alice Wallenbergs Stiftelse, Vetenskapsrådet, China Scholarship Council, Science for Life Laboratory, Medical Research Council, HORIZON EUROPE Marie Sklodowska-Curie Actions
Awards: Mitochondrial structure, integrity and function in inflammatory diseases, The role of CTCF and cohesin in leukemia development, Lipid Stabilisation and Modulation of Membrane Proteins, Molecular basis of sodium channel function and modulation, G3010212676, G3471652666, G3584431731, Correlative cytometry to measure biophysical properties of cells in health and disease, Restoring immune fitness through biophysical manipulations, Characterizing ligand-protein interactions with a cryo-EM data-driven modeling approach, Regulation & Desensitization of Ligand-Gated Ion Channels
OpenAlex ID: W7131392829