Peddada, Nagesh and Sagar, Amin and Rathore, Yogendra S and Choudhary, Vikas and Pattnaik, U Bharat K and Khatri, Neeraj and Garg, Renu and Ganguly, Ashish (2013) Global shapes of F-actin depolymerization-competent minimal gelsolins: insight into the role of g2-g3 linker in pH/Ca2+ insensitivity of the first half. The Journal of biological chemistry, 288 (39). pp. 28266-82. ISSN 1083-351X
Full text not available from this repository. (Request a copy)Abstract
Because of its ability to rapidly depolymerize F-actin, plasma gelsolin has emerged as a therapeutic molecule in different disease conditions. High amounts of exogenous gelsolin are, however, required to treat animal models of different diseases. Knowing that the F-actin depolymerizing property of gelsolin resides in its N terminus, we made several truncated versions of plasma gelsolin. The smaller versions, particularly the one composed of the first 28-161 residues, depolymerized the F-actin much faster than the native gelsolin and other truncates at the same molar ratios. Although G1-G3 loses its dependence on Ca(2+) or low pH for the actin depolymerization function, interestingly, G1-G2 and its smaller versions were found to regain this requirement. Small angle x-ray scattering-based shape reconstructions revealed that G1-G3 adopts an open shape in both the presence and the absence of Ca(2+) as well as low pH, whereas G1-G2 and residues 28-161 prefer collapsed states in Ca(2+)-free conditions at pH 8. The mutations in the g2-g3 linker resulted in the calcium sensitivity of the mutant G1-G3 for F-actin depolymerization activity, although the F-actin-binding sites remained exposed in the mutant G1-G3 as well as in the smaller truncates even in the Ca(2+)-free conditions at pH 8. Furthermore, unlike wild type G1-G3, calcium-sensitive mutants of G1-G3 acquired closed shapes in the absence of free calcium, implying a role of g2-g3 linker in determining the open F-actin depolymerizing-competent shape of G1-G3 in this condition. We demonstrate that the mobility of the G1 domain, essential for F-actin depolymerization, is indirectly regulated by the gelsolin-like sequence of g2-g3 linker.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | Actin; Minimal Gelsolin; Molecular Modeling; Protein Engineering; Sepsis; Small Angle X-ray Scattering; X-ray Scattering; ab Initio Modeling |
| Depositing User: | Dr. K.P.S.Sengar |
| Date Deposited: | 11 Feb 2015 09:42 |
| Last Modified: | 22 Jul 2015 03:44 |
| URI: | http://crdd.osdd.net/open/id/eprint/1621 |
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