ArticleScientific reports2020
Steered molecular dynamic simulations reveal Marfan syndrome mutations disrupt fibrillin-1 cbEGF domain mechanosensitive calcium binding.
Article in Scientific reports, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 18 citations in OpenAlex.
- Genotype-associated structural and nanomechanical alterations of aortic fibrillin-1 microfibrils in Marfan syndrome.Matrix biology plus · 2026Article
- Genetic and molecular mechanisms of hereditary thoracic aortic aneurysm and dissection (Review).Molecular medicine reports · 2026Review
- Structural and Signaling Mechanisms of Aortic Wall Failure in Heritable Thoracic Aortic Disease.Cells · 2026Review
- Structural basis of EGF-repeat O-glucosylation by the protein O-glucosyltransferase POGLUT2.The Journal of biological chemistry · 2026Article
- On-demand delivery of fibulin-1 protects the basement membrane during cyclic stretching in C. elegans.Developmental cell · 2025Article
- Review
- Regulation of Joint Tissues and Joint Function: Is There Potential for Lessons to Be Learned Regarding Regulatory Control from Joint Hypermobility Syndromes?International journal of molecular sciences · 2025Review
- Causative role of a novel intronic indel variant in FBN1 and maternal germinal mosaicism in Marfan syndrome.Orphanet journal of rare diseases · 2024Article
- Clinical and genetic findings in Chinese families with congenital ectopia lentis.Molecular genetics & genomic medicine · 2023Article
- Extracellular mechanotransduction.The Journal of general physiology · 2022Article
- Structural studies of elastic fibre and microfibrillar proteins.Matrix biology plus · 2021Article
- Fascial Nomenclature: Update 2021, Part 1.Cureus · 2021Review
- Cysteine Substitution and Calcium-Binding Mutations inFrontiers in cell and developmental biology · 2021Article
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Authors and funding
3 authors at 2 institutions in 1 country.
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Abstract
Marfan syndrome (MFS) is a highly variable genetic connective tissue disorder caused by mutations in the calcium binding extracellular matrix glycoprotein fibrillin-1. Patients with the most severe form of MFS (neonatal MFS; nMFS) tend to have mutations that cluster in an internal region of fibrillin-1 called the neonatal region. This region is predominantly composed of eight calcium-binding epidermal growth factor-like (cbEGF) domains, each of which binds one calcium ion and is stabilized by three highly conserved disulfide bonds. Crucially, calcium plays a fundamental role in stabilizing cbEGF domains. Perturbed calcium binding caused by cbEGF domain mutations is thus thought to be a central driver of MFS pathophysiology. Using steered molecular dynamics (SMD) simulations, we demonstrate that cbEGF domain calcium binding decreases under mechanical stress (i.e. cbEGF domains are mechanosensitive). We further demonstrate the disulfide bonds in cbEGF domains uniquely orchestrate protein unfolding by showing that MFS disulfide bond mutations markedly disrupt normal mechanosensitive calcium binding dynamics. These results point to a potential mechanosensitive mechanism for fibrillin-1 in regulating extracellular transforming growth factor beta (TGFB) bioavailability and microfibril integrity. Such mechanosensitive "smart" features may represent novel mechanisms for mechanical hemostasis regulation in extracellular matrix that are pathologically activated in MFS.
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