5o2z
From Proteopedia
Domain swap dimer of the G167R variant of gelsolin second domain
Structural highlights
Disease[GELS_HUMAN] Defects in GSN are the cause of amyloidosis type 5 (AMYL5) [MIM:105120]; also known as familial amyloidosis Finnish type. AMYL5 is a hereditary generalized amyloidosis due to gelsolin amyloid deposition. It is typically characterized by cranial neuropathy and lattice corneal dystrophy. Most patients have modest involvement of internal organs, but severe systemic disease can develop in some individuals causing peripheral polyneuropathy, amyloid cardiomyopathy, and nephrotic syndrome leading to renal failure.[1] [2] [3] [4] Function[GELS_HUMAN] Calcium-regulated, actin-modulating protein that binds to the plus (or barbed) ends of actin monomers or filaments, preventing monomer exchange (end-blocking or capping). It can promote the assembly of monomers into filaments (nucleation) as well as sever filaments already formed. Plays a role in ciliogenesis.[5] Publication Abstract from PubMedAGel 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 characterization 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. Gelsolin pathogenic Gly167Arg mutation promotes domain-swap dimerization of the protein.,Boni F, Milani M, Barbiroli A, Diomede L, Mastrangelo E, de Rosa M Hum Mol Genet. 2017 Oct 23. doi: 10.1093/hmg/ddx383. PMID:29069428[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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