Structural Basis for pH-mediated Regulation of F-actin Severing by Gelsolin Domain 1

Jing Song Fan, Honzhen Goh, Ke DIng, Bo Xue, Robert C. Robinson, Daiwen Yang

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish
Article number45230
JournalScientific reports
Volume7
DOIs
Publication statusPublished - Mar 28 2017
Externally publishedYes

Fingerprint

Gelsolin
Actins
Acidic Amino Acids
Histidine
Mutagenesis

ASJC Scopus subject areas

  • General

Cite this

Structural Basis for pH-mediated Regulation of F-actin Severing by Gelsolin Domain 1. / Fan, Jing Song; Goh, Honzhen; DIng, Ke; Xue, Bo; Robinson, Robert C.; Yang, Daiwen.

In: Scientific reports, Vol. 7, 45230, 28.03.2017.

Research output: Contribution to journalArticle

Fan, Jing Song ; Goh, Honzhen ; DIng, Ke ; Xue, Bo ; Robinson, Robert C. ; Yang, Daiwen. / Structural Basis for pH-mediated Regulation of F-actin Severing by Gelsolin Domain 1. In: Scientific reports. 2017 ; Vol. 7.
@article{2b856a4a016e4d31bd18a21d85ed955e,
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.",
author = "Fan, {Jing Song} and Honzhen Goh and Ke DIng and Bo Xue and Robinson, {Robert C.} and Daiwen Yang",
year = "2017",
month = "3",
day = "28",
doi = "10.1038/srep45230",
language = "English",
volume = "7",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Structural Basis for pH-mediated Regulation of F-actin Severing by Gelsolin Domain 1

AU - Fan, Jing Song

AU - Goh, Honzhen

AU - DIng, Ke

AU - Xue, Bo

AU - Robinson, Robert C.

AU - Yang, Daiwen

PY - 2017/3/28

Y1 - 2017/3/28

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85016647364&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85016647364&partnerID=8YFLogxK

U2 - 10.1038/srep45230

DO - 10.1038/srep45230

M3 - Article

C2 - 28349924

AN - SCOPUS:85016647364

VL - 7

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

M1 - 45230

ER -