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

DOI: 10.1038/ncomms9254 DOI Help
PMID: 26365202 PMID Help

Authors: Sakesit Chumnarnsilpa (University of Oxford) , Robert C. Robinson (A*STAR) , Jonathan Grimes (Division of Structural Biology, University of Oxford, Diamond Light Source) , Cedric Leyrat (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 6

State: Published (Approved)
Published: September 2015

Open Access Open Access

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.

Subject Areas: Biology and Bio-materials

Facility: ESRF