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.
Highlights
Gelsolin is the prototype of a large superfamily of proteins, responsible for the assembly, disassembly and scavenging of actin filaments by means of its severing and capping activities [1,2]
A similar approach was here applied to dissect the molecular bases of the pathogenicity of the other variant responsible for gelsolin-related renal amyloidosis
To achieve a more quantitative description of the process, we studied dimerization by dynamic light scattering (DLS) under the same conditions used in gel filtration (GF) experiments (Fig. 3C)
Summary
Gelsolin is the prototype of a large superfamily of proteins, responsible for the assembly, disassembly and scavenging of actin filaments by means of its severing and capping activities [1,2]. The active conformation is highly dynamic as most of the interdomain contacts are lost and the domains are linked only by flexible stretches of the polypeptide chain [9]. For this reason, no high-resolution structure of calcium-activated gelsolin has been reported so far and structural biologists have to mainly rely on the study of isolated domains to gain insight into gelsolin physiopathology [3,4,6].
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