title: Structural Basis for pH-mediated Regulation of F-actin Severing by Gelsolin Domain 1.
abstract: Six-domain gelsolin regulates actin structural dynamics through its abilities to sever, cap and uncap F-actin. These activities are modulated by various cellular parameters like Ca2+and pH. Until now, only the molecular activation mechanism of gelsolin by Ca2+has been understood relatively well. The fragment comprising the first domain and six residues from the linker region into the second domain has been shown to be similar to the full-length protein in F-actin severing activity in the absence of Ca2+at pH 5. To understand how this gelsolin fragment is activated for F-actin severing by lowering pH, we solved its NMR structures at both pH 7.3 and 5 in the absence of Ca2+and measured the pKa values of acidic amino acid residues and histidine residues. The overall structure and dynamics of the fragment are not affected significantly by pH. Nevertheless, local structural changes caused by protonation of His29 and Asp109 result in the activation on lowering the pH, and protonation of His151 directly effects filament binding since it resides in the gelsolin/actin interface. Mutagenesis studies support that His29, Asp109 and His151 play important roles in the pH-dependent severing activity of the gelsolin fragment.
authors.affiliation: Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, 117543, Singapore.
authors.forename: Jing-Song
authors.initials: JS
authors.lastname: Fan
authors.affiliation: Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, 117543, Singapore.
authors.forename: Honzhen
authors.initials: H
authors.lastname: Goh
authors.affiliation: Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Singapore.
authors.forename: Ke
authors.initials: K
authors.lastname: Ding
authors.affiliation: Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Singapore.
authors.forename: Bo
authors.initials: B
authors.lastname: Xue
authors.affiliation: Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Singapore.|Department of Biochemistry, National University of Singapore, Singapore.|NTU Institute of Structural Biology, Nanyang Technological University, 59 Nanyang Drive, 636921, Singapore.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Robinson
authors.affiliation: Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, 117543, Singapore.
authors.forename: Daiwen
authors.initials: D
authors.lastname: Yang
mesh_terms: D000199:Actins / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D018260:Gelsolin / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D062105:Molecular Docking Simulation; D011485:Protein Binding
chemical_list: D000199:Actins; D018260:Gelsolin; D002118:Calcium