ArticleHuman molecular genetics2018
Gelsolin pathogenic Gly167Arg mutation promotes domain-swap dimerization of the protein.
Article in Human molecular genetics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 18 citations in OpenAlex.
- A molecular perspective of gelsolin amyloidosis: An old foe with new faces.Cellular and molecular life sciences : CMLS · 2026Review
- Rational Design of a Peptidomimetic Inhibitor of Gelsolin Amyloid Aggregation.International journal of molecular sciences · 2022Article
- Aggregation of gelsolin wild-type and G167K/R, N184K, and D187N/Y mutant peptides and inhibition.Molecular and cellular biochemistry · 2021Article
- 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
- Renal amyloidosis: an update on diagnosis and pathogenesis.Protoplasma · 2020Review
- Proteomic profiling and identification of significant markers from high-grade osteosarcoma after cryotherapy and irradiation.Scientific reports · 2020Article
- Analyses Mutations inFrontiers in aging neuroscience · 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
- The role of gelsolin domain 3 in familial amyloidosis (Finnish type).Proceedings of the National Academy of Sciences of the United States of America · 2019Article
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
AGel amyloidosis is a genetic degenerative disease characterized by the deposition of insoluble gelsolin protein aggregates in different tissues. Until recently, this disease was associated with two mutations of a single residue (Asp187 to Asn/Tyr) in the second domain of the protein. The general opinion is that pathogenic variants are not per se amyloidogenic but rather that the mutations trigger an aberrant proteolytic cascade, which results in the production of aggregation prone fragments. Here, we report the crystal structure of the second domain of gelsolin carrying the recently identified Gly167Arg mutation. This mutant dimerizes through a three-dimensional domain swapping mechanism, forming a tight but flexible assembly, which retains the structural topology of the monomer. To date, such dramatic conformational changes of this type have not been observed. Structural and biophysical characterizations reveal that the Gly167Arg mutation alone is responsible for the monomer to dimer transition and that, even in the context of the full-length protein, the pathogenic variant is prone to form dimers. These data suggest that, in addition to the well-known proteolytic-dependent mechanism, an alternative oligomerization pathway may participate in gelsolin misfolding and aggregation. We propose to integrate this alternative pathway into the current model of the disease that may also be relevant for other types of AGel amyloidosis, and other related diseases with similar underlying pathological mechanisms.
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