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The S100A1 protein regulates cardiomyocyte function through its binding of calcium (Ca2+) and target proteins, including titin, SERCA, and RyR. S100A1 presents two Ca2+ binding domains, a high-affinity canonical EF-hand (cEF) and a low-affinity pseudo EF-hand (pEF), that control S100A1 activation. For wild-type S100A1, both EF hands must be bound by Ca2+ to form the open state necessary for target peptide binding, which requires unphysiological high sub-millimolar Ca2+ levels. However, there is evidence that post-translational modifications at Cys85 may facilitate the formation of the open state at sub-saturating Ca2+ concentrations. Hence, post-translational modifications of S100A1 could potentially increase the Ca2+-sensitivity of binding protein targets, and thereby modulate corresponding signaling pathways. In this study, we examine the mechanism of S100A1 open-closed gating via molecular dynamics simulations to determine the extent to which Cys85 functionalization, namely via redox reactions, controls the relative population of open states at sub-saturating Ca2+ and capacity to bind peptides. We further characterize the protein's ability to bind a representative peptide target, TRKT12 and relate this propensity to published competition assay data. Our simulation results indicate that functionalization of Cys85 may stabilize the S100A1 open state at physiological, micromolar Ca2+ levels. Our conclusions support growing evidence that S100A1 serves as a signaling hub linking Ca2+ and redox signaling pathways.

Background: Osteosarcoma is the most common primary malignant tumor of bone. Abnormal expression of S100A1 protein is closely related to the occurrence and development of malignant tumors. However, S100A1 in osteosarcoma has not been studied., Methods: All osteosarcoma tissues were collected from patients who received surgical therapy at the Affiliated Hospital of Inner Mongolia Medical University, China in 2020. QRT-PCR and western blot assays were used to detect the expression of S100A1 in osteosarcoma tissues and cells. The negative effect of S100A1 on osteosarcoma cell growth was confirmed by vitro and vivo experiments., Results: S100A1 inhibited the growth of osteosarcoma cells in vitro. Overexpression of S100A1 may inhibit the proliferation of osteosarcoma cells by preventing the activation of AKT signaling pathway by western blot assay. Finally, animal experiments confirmed that overexpression of S100A1 could inhibit the proliferation of osteosarcoma cells. Overexpression of S100A1 obtained better survival benefit in mice., Conclusion: Our findings provided a new insight to the treatment of osteosarcoma. It also raised the possibility that S100A1 could be used in targeted therapies for osteosarcoma., Competing Interests: Conflict of Interest The authors declare that there is no conflict of interest., (Copyright © 2022 Xing et al. Published by Tehran University of Medical Sciences.)