Calcium-controlled conformational choreography in the N-terminal half of adseverin

Sakesit Chumnarnsilpa (), Robert C. Robinson, Jonathan M. Grimes () and Cedric Leyrat ()
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Sakesit Chumnarnsilpa: University of Oxford, Henry Wellcome Building for Genomic Medicine
Robert C. Robinson: Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research)
Jonathan M. Grimes: University of Oxford, Henry Wellcome Building for Genomic Medicine
Cedric Leyrat: University of Oxford, Henry Wellcome Building for Genomic Medicine

Nature Communications, 2015, vol. 6, issue 1, 1-13

Abstract: Abstract Adseverin is a member of the calcium-regulated gelsolin superfamily of actin-binding proteins. Here we report the crystal structure of the calcium-free N-terminal half of adseverin (iA1–A3) and the Ca2+-bound structure of A3, which reveal structural similarities and differences with gelsolin. Solution small-angle X-ray scattering combined with ensemble optimization revealed a dynamic Ca2+-dependent equilibrium between inactive, intermediate and active conformations. Increasing calcium concentrations progressively shift this equilibrium from a main population of inactive conformation to the active form. Molecular dynamics simulations of iA1–A3 provided insights into Ca2+-induced destabilization, implicating a critical role for the A2 type II calcium-binding site and the A2A3 linker in the activation process. Finally, mutations that disrupt the A1/A3 interface increase Ca2+-independent F-actin severing by A1–A3, albeit at a lower efficiency than observed for gelsolin domains G1–G3. Together, these data address the calcium dependency of A1–A3 activity in relation to the calcium-independent activity of G1–G3.

Date: 2015
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DOI: 10.1038/ncomms9254

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