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  current news   Press   selected story    
     
  20 October 2015  
 
Calcium-controlled conformational choreography in the N-terminal half of adseverin
 
 




Authors
Sakesit Chumnarnsilpa1,2,3, Robert C. Robinson1,4, Jonathan M. Grimes2,5 and Cedric Leyrat2

1 Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research),   Biopolis, Singapore 138673, Singapore
2 Division of Structural Biology, University of Oxford, Henry Wellcome Building for Genomic Medicine,   Oxford OX3 7BN, UK
3 School of Biochemistry, Institute of Science, Suranaree University of Technology, 111 University   Avenue, Muang, Nakhon Ratchasima 30000, Thailand
4 Department of Biochemistry, National University of Singapore, 8 Medical Drive, Singapore 117597,   Singapore
5 Science Division, Diamond Light Source Ltd, Diamond House, Harwell Science and Innovation Campus,   Didcot, Oxfordshire OX11 0DE, UK

Published in Nature Communications on 14 September 2015.
http://www.nature.com/ncomms/2015/150914/ncomms9254/full/ncomms9254.html

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.

Figure:

Figure legend: Model for A1–A3 transition between the inactive and active (actin-binding competent) states. The release of the A1/A3 latch from the inactive form (I) leads to a first intermediate (Int1), followed by the loss of the A1A2 interface (Int2). Finally, the calcium-stabilized interface between A2 and A3 is formed, resulting in the active conformation.

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