Abstract
Gelsolin modulates the actin cytoskeleton in the cytoplasm and clears the circulation of stray filaments. In vitro, gelsolin cleaves, nucleates and caps actin filaments, activities that are calcium-dependent. Both cellular and secreted forms share a sequence of 730 residues comprising six homologous modules termed G1-G6. A disulphide bond is formed in secreted G2, whereas in the cytoplasm it remains reduced. A point mutation in G2 causes an amyloidosis with neurological, ophthalmological and dermatological symptoms. This mutation does not affect the cytoplasmic form, while the secreted form is proteolysed. As a first step towards understanding how gelsolin folds and functions in different cellular compartments, we have characterized at equilibrium the urea-induced unfolding of G1 and G2, with or without calcium and/or disulphide bond. G1 and G2 both exhibit two-state unfolding behaviour and are stabilized by calcium. The disulphide bond also contributes to the stability of G2. In the absence of Ca(2+) and disulphide bond, G2 adopts a non-native conformation, suggesting that folding of G2 in the cytoplasm relies on the presence of surrounding modules or other molecular partners.
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