A novel hotspot of gelsolin instability triggers an alternative mechanism of amyloid aggregation
Authors/Creators
- 1. CNR
- 2. Istituto di Ricerche Farmacologiche Mario Negri, IRCCS
- 3. Università degli Studi di Milano
- 4. Università Ljubljana
Description
Gelsolin comprises six homologous domains, named G1 to G6. Single point substitutions in this protein
are responsible for AGel amyloidosis, a hereditary disease causing progressive corneal lattice dystrophy,
cutis laxa, and polyneuropathy. Although several different amyloidogenic variants of gelsolin have been
identified, only the most common mutants present in the G2 domain have been thoroughly characterized,
leading to clarification of the functional mechanism. The molecular events underlying the pathological
aggregation of 3 recently identified mutations, namely A551P, E553K and M517R, all localized at the
interface between G4 and G5, are here explored for the first time. Structural studies point to destabilization
of the interface between G4 and G5 due to three structural determinants: b-strand breaking, steric
hindrance and/or charge repulsion, all implying impairment of interdomain contacts. Such rearrangements
decrease the temperature and pressure stability of gelsolin but do not alter its susceptibility to
furin cleavage, the first event in the canonical aggregation pathway. These variants also have a greater
tendency to aggregate in the unproteolysed forms and exhibit higher proteotoxicity in a C. elegansbased
assay. Our data suggest that aggregation of G4G5 variants follows an alternative, likely
proteolysis-independent, pathway.
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