Modulation of gelsolin function. Activation at low pH overrides Ca2+ requirement - PubMed (original) (raw)

. 1993 Apr 25;268(12):8999-9004.

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Modulation of gelsolin function. Activation at low pH overrides Ca2+ requirement

J A Lamb et al. J Biol Chem. 1993.

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Abstract

The activation of gelsolin by calcium has been postulated to be involved in the receptor-mediated reorganization of the actin cytoskeleton, but cytoskeletal reorganization can also occur in cells with intracellular Ca2+ clamped at nanomolar levels. Fluorescence measurements using Fura-2 show that at pH 7.4, the Ca2+ requirement for gelsolin activation in vitro is higher than previously reported, with half-maximal activation of severing and nucleation occurring at 10 microM Ca2+. The Ca2+ requirement for gelsolin activity decreases at more acid pH and is approximately 3 microM at pH 6.5. At pH below 6.0, gelsolin no longer requires Ca2+ for activity and severs actin filaments, binds two actin monomers, and nucleates filament formation in EGTA-containing solutions. The pH-activated severing activity is inhibited by mixed lipid vesicles containing phosphatidylinositol 4,5-bisphosphate. A Ca(2+)-sensitive fragment consisting of the first 135 amino acids of human cytoplasmic gelsolin also demonstrates severing activity at pH < 6.0 in the absence of Ca2+. In contrast, the gelsolin homologs severin and villin maintain Ca2+ regulation of severing activity at low pH. These differences suggest that activation of gelsolin at low pH cannot be explained merely by destabilization of F-actin. The difference in diffusion constants of gelsolin measured at pH 5.5 and 6.5, as determined by dynamic light scattering, suggests that the molecule undergoes a shape change similar to that reported upon binding Ca2+ at neutral pH. These results suggest a mechanism by which gelsolin may be activated in vivo under conditions where Ca2+ transients do not occur.

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