ArticleProceedings of the National Academy of Sciences of the United States of America2019
The role of gelsolin domain 3 in familial amyloidosis (Finnish type).
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers, 1 of them a synthesis that pooled it.
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Who cites it
13 citing papers in PubMed, 1 synthesis or guideline pooled it, 18 citations in OpenAlex.
- Research Progress and Applications of Multivalent, Multispecific and Modified Nanobodies for Disease Treatment.Frontiers in immunology · 2021Pooled it
- A molecular perspective of gelsolin amyloidosis: An old foe with new faces.Cellular and molecular life sciences : CMLS · 2026Review
- Plant Hormone Cytokinin as Aggregation Modulator of Gelsolin Amyloidosis.Journal of peptide science : an official publication of the European Peptide Society · 2025Article
- Accurate and Efficient SAXS/SANS Implementation Including Solvation Layer Effects Suitable for Molecular Simulations.Journal of chemical theory and computation · 2023Article
- Article
- Molecular Dynamics Study of the Curvature-Driven Interactions between Carbon-Based Nanoparticles and Amino Acids.Molecules (Basel, Switzerland) · 2023Article
- Report of two pedigrees with heterozygous HTRA1 variants-related cerebral small vessel disease and literature review.Molecular genetics & genomic medicine · 2022Review
- Inverse Boltzmann Iterative Multi-Scale Molecular Dynamics Study between Carbon Nanotubes and Amino Acids.Molecules (Basel, Switzerland) · 2022Article
- Clinical and Histopathological Features of Gelsolin Amyloidosis Associated with a NovelInternational journal of molecular sciences · 2021Article
- A novel hotspot of gelsolin instability triggers an alternative mechanism of amyloid aggregation.Computational and structural biotechnology journal · 2021Article
- Edge Strand Dissociation and Conformational Changes in Transthyretin under Amyloidogenic Conditions.Biophysical journal · 2020Article
- The structure of N184K amyloidogenic variant of gelsolin highlights the role of the H-bond network for protein stability and aggregation properties.European biophysics journal : EBJ · 2020Article
- Analyses Mutations inFrontiers in aging neuroscience · 2020Article
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Authors and funding
8 authors at 4 institutions in 6 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
In the disease familial amyloidosis, Finnish type (FAF), also known as AGel amyloidosis (AGel), the mechanism by which point mutations in the calcium-regulated actin-severing protein gelsolin lead to furin cleavage is not understood in the intact protein. Here, we provide a structural and biochemical characterization of the FAF variants. X-ray crystallography structures of the FAF mutant gelsolins demonstrate that the mutations do not significantly disrupt the calcium-free conformations of gelsolin. Small-angle X-ray-scattering (SAXS) studies indicate that the FAF calcium-binding site mutants are slower to activate, whereas G167R is as efficient as the wild type. Actin-regulating studies of the gelsolins at the furin cleavage pH (6.5) show that the mutant gelsolins are functional, suggesting that they also adopt relatively normal active conformations. Deletion of gelsolin domains leads to sensitization to furin cleavage, and nanobody-binding protects against furin cleavage. These data indicate instability in the second domain of gelsolin (G2), since loss or gain of G2-stabilizing interactions impacts the efficiency of cleavage by furin. To demonstrate this principle, we engineered non-FAF mutations in G3 that disrupt the G2-G3 interface in the calcium-activated structure. These mutants led to increased furin cleavage. We carried out molecular dynamics (MD) simulations on the FAF and non-FAF mutant G2-G3 fragments of gelsolin. All mutants showed an increase in the distance between the center of masses of the 2 domains (G2 and G3). Since G3 covers the furin cleavage site on G2 in calcium-activated gelsolin, this suggests that destabilization of this interface is a critical step in cleavage.
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