Human Cofilin2: Towards the Comprehension of the Molecular Mechanism

Cofilin is an evolutionarily highly conserved protein which belongs to the ADF/cofilin family involved in the regulation of actin-filament dynamics depolymerizing and/or severing actin filaments. Phosphorylation on serine 3 inactivates cofilin [1,2] by generation of a charge repulsion between cofilin and actin, which is thought to occur without altering the protein structure [3]. In terms of physiological functions, cofilin- 2 is the least understood member of this protein family, which is present predominantly in skeletal and cardiac muscle [4-6]. In reducing media, even phosphatidylinositol 4,5-bisphosphate-bound cofilin is active, leading to actin dynamics in the vicinity of the plasma membrane. This mechanism has been proposed to explain why dendritic cells that are able to increase the thiol pool in antigen-specific T cells enable T cell activation even under oxidative stress conditions. On the contrary, cofilin is inactivated by oxidation, provoking T-cell hyporesponsiveness or necrotic-like programmed cell death [7]. In this study we present the production, the physico-chemical characterization and the modelled structure of the wt and the phosphorylated-mimicking S3D variant of the human cofilin2. The study allowed the evaluation of the structural differences between the active and the inactive protein while an electrochemical and fluorometric approach provided new data to increase in the understanding of the cofilin-action mechanism. 1. Agnew BJ, Minamide LS, Bamburg JR. J Biol Chem 1995; 270:17582–17587. 2. Moriyama K, Iida K, Yahara I. Genes Cells 1996; 1:73–86. 3. Blanchoin L, Robinson RC, Choe S, Pollard TD. J Mol Biol 2000;295:203–211. 4. Bernstein BW, Bamburg JR. Trends Cell Biol 2010;20(4):187–95. 5. Agrawal PB, Joshi M, Savic Tetal.. Hum Mol Genet. 2012 May 15; 21(10): 2341–2356 6. C. Thirion et al. (Eur. J. Biochem. 268)-2001 7. Y. Samstag, I. John, G. H. Wabnitz Immunological Reviews 256 (2013) 30-47.