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Title: Targeted molecular dynamics simulation studies of calcium binding and conformational change in the C-terminal half of gelsolin

Abstract

Gelsolin consists of six related domains (G1-G6) and the C-terminal half (G4-G6) acts as a calcium sensor during the activation of the whole molecule, a process that involves large domain movements. In this study, we used targeted molecular dynamics simulations to elucidate the conformational transitions of G4-G6 at an atomic level. Domains G4 and G6 are initially ruptured, followed by a rotation of G6 by {approx}90{sup o}, which is the dominant conformational change. During this period, local conformational changes occur at the G4 and G5 calcium-binding sites, facilitating large changes in interdomain distances. Alterations in the binding affinities of the calcium ions in these three domains appear to be related to local conformational changes at their binding sites. Analysis of the relative stabilities of the G4-G6-bound calcium ions suggests that they bind first to G6, then to G4, and finally to G5.

Authors:
 [1];  [2];  [3];  [1];  [2];  [1];  [2];  [4];  [5]
  1. Department of Microbiology, University of Ulsan College of Medicine, 388-1 PoongNap-dong Songpa-goo, Seoul 138-736 (Korea, Republic of)
  2. (Korea, Republic of)
  3. Institute of Molecular and Cell Biology, Proteos, 61 Biopolis Drive, 138673 Singapore (Singapore)
  4. Department of Microbiology, University of Ulsan College of Medicine, 388-1 PoongNap-dong Songpa-goo, Seoul 138-736 (Korea, Republic of) and Research Institute for Biomacromolecules, University of Ulsan College of Medicine, 388-1 PoongNap-dong Songpa-goo, Seoul 138-736 (Korea, Republic of). E-mail: ykkim@amc.seoul.kr
  5. Department of Physiology, University of Ulsan College of Medicine, 388-1 PoongNap-dong Songpa-goo, Seoul 138-736 (Korea, Republic of) and Research Institute for Biomacromolecules, University of Ulsan College of Medicine, 388-1 PoongNap-dong Songpa-goo, Seoul 138-736 (Korea, Republic of). E-mail: hchoe@amc.seoul.kr
Publication Date:
OSTI Identifier:
20798887
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 342; Journal Issue: 3; Other Information: DOI: 10.1016/j.bbrc.2006.01.184; PII: S0006-291X(06)00204-X; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; CALCIUM; CALCIUM IONS; CONFORMATIONAL CHANGES; MOLECULAR DYNAMICS METHOD; MOLECULES; SIMULATION

Citation Formats

Lee, Hui Sun, Research Institute for Biomacromolecules, University of Ulsan College of Medicine, 388-1 PoongNap-dong Songpa-goo, Seoul 138-736, Robinson, Robert Charles, Joo, Chul Hyun, Research Institute for Biomacromolecules, University of Ulsan College of Medicine, 388-1 PoongNap-dong Songpa-goo, Seoul 138-736, Lee, Heuiran, Research Institute for Biomacromolecules, University of Ulsan College of Medicine, 388-1 PoongNap-dong Songpa-goo, Seoul 138-736, Kim, Yoo Kyum, and Choe, Han. Targeted molecular dynamics simulation studies of calcium binding and conformational change in the C-terminal half of gelsolin. United States: N. p., 2006. Web. doi:10.1016/j.bbrc.2006.01.184.
Lee, Hui Sun, Research Institute for Biomacromolecules, University of Ulsan College of Medicine, 388-1 PoongNap-dong Songpa-goo, Seoul 138-736, Robinson, Robert Charles, Joo, Chul Hyun, Research Institute for Biomacromolecules, University of Ulsan College of Medicine, 388-1 PoongNap-dong Songpa-goo, Seoul 138-736, Lee, Heuiran, Research Institute for Biomacromolecules, University of Ulsan College of Medicine, 388-1 PoongNap-dong Songpa-goo, Seoul 138-736, Kim, Yoo Kyum, & Choe, Han. Targeted molecular dynamics simulation studies of calcium binding and conformational change in the C-terminal half of gelsolin. United States. doi:10.1016/j.bbrc.2006.01.184.
Lee, Hui Sun, Research Institute for Biomacromolecules, University of Ulsan College of Medicine, 388-1 PoongNap-dong Songpa-goo, Seoul 138-736, Robinson, Robert Charles, Joo, Chul Hyun, Research Institute for Biomacromolecules, University of Ulsan College of Medicine, 388-1 PoongNap-dong Songpa-goo, Seoul 138-736, Lee, Heuiran, Research Institute for Biomacromolecules, University of Ulsan College of Medicine, 388-1 PoongNap-dong Songpa-goo, Seoul 138-736, Kim, Yoo Kyum, and Choe, Han. Fri . "Targeted molecular dynamics simulation studies of calcium binding and conformational change in the C-terminal half of gelsolin". United States. doi:10.1016/j.bbrc.2006.01.184.
@article{osti_20798887,
title = {Targeted molecular dynamics simulation studies of calcium binding and conformational change in the C-terminal half of gelsolin},
author = {Lee, Hui Sun and Research Institute for Biomacromolecules, University of Ulsan College of Medicine, 388-1 PoongNap-dong Songpa-goo, Seoul 138-736 and Robinson, Robert Charles and Joo, Chul Hyun and Research Institute for Biomacromolecules, University of Ulsan College of Medicine, 388-1 PoongNap-dong Songpa-goo, Seoul 138-736 and Lee, Heuiran and Research Institute for Biomacromolecules, University of Ulsan College of Medicine, 388-1 PoongNap-dong Songpa-goo, Seoul 138-736 and Kim, Yoo Kyum and Choe, Han},
abstractNote = {Gelsolin consists of six related domains (G1-G6) and the C-terminal half (G4-G6) acts as a calcium sensor during the activation of the whole molecule, a process that involves large domain movements. In this study, we used targeted molecular dynamics simulations to elucidate the conformational transitions of G4-G6 at an atomic level. Domains G4 and G6 are initially ruptured, followed by a rotation of G6 by {approx}90{sup o}, which is the dominant conformational change. During this period, local conformational changes occur at the G4 and G5 calcium-binding sites, facilitating large changes in interdomain distances. Alterations in the binding affinities of the calcium ions in these three domains appear to be related to local conformational changes at their binding sites. Analysis of the relative stabilities of the G4-G6-bound calcium ions suggests that they bind first to G6, then to G4, and finally to G5.},
doi = {10.1016/j.bbrc.2006.01.184},
journal = {Biochemical and Biophysical Research Communications},
number = 3,
volume = 342,
place = {United States},
year = {Fri Apr 14 00:00:00 EDT 2006},
month = {Fri Apr 14 00:00:00 EDT 2006}
}
  • S. Typhimurium can induce both humoral and cell-mediated responses when establishing itself in the host. These responses are primarily stimulated against the lipopolysaccharide and major outer membrane (OM) proteins. OmpA is one of these major OM proteins. It comprises a N-terminal eight-stranded b-barrel trans membrane domain and a C-terminal domain (OmpACTD). The OmpACTD and its homologs are believed to bind to peptidoglycan (PG) within the periplasm, maintaining bacterial osmotic homeostasis and modulating the permeability and integrity of the OM. Here we present the first crystal structures of the OmpACTD from two pathogens: S. Typhimurium (STOmpACTD) in open and closed formsmore » and causative agent of Lyme Disease Borrelia burgdorferi (BbOmpACTD), in closed form. In the open form of STOmpACTD, an aspartic acid residue from a long b2-a3 loop points into the binding pocket, suggesting that an anion group such as a carboxylate group from PG is favored at the binding site. In the closed form of STOmpACTD and in the structure of BbOmpACTD, a sulfate group from the crystallization buffer is tightly bound at the binding site. The differences between the closed and open forms of STOmpACTD, suggest a large conformational change that includes an extension of a3 helix by ordering a part of b2-a3 loop. We propose that the sulfate anion observed in these structures mimics the carboxylate group of PG when bound to STOmpACTD suggesting PG-anchoring mechanism. In addition, the binding of PG or a ligand mimic may enhance dimerization of STOmpACTD, or possibly that of full length STOmpA.« less
  • S. Typhimurium can induce both humoral and cell-mediated responses when establishing itself in the host. These responses are primarily stimulated against the lipopolysaccharide and major outer membrane (OM) proteins of the bacterium. OmpA is one of these major OM proteins. It comprises a N-terminal eight-stranded -barrel membrane domain and a C-terminal so-called OmpA C-terminal domain (OmpACTD). The OmpACTD and its homologs are believed to bind to peptidoglycan (PG) within the periplasm, maintaining bacterial osmotic homeostasis and modulating the permeability and integrity of the outer membrane. Here we present the structures of two forms of the OmpACTD of S. Typhimurium (STOmpACTD)more » and one structure of the less-studied OmpACTD of Borrelia burgdorferi (BbOmpACTD). In the open form of STOmpACTD, an aspartic acid residue from a long 2-3 loop points into the binding pocket, suggesting that an anion group such as a carboxylate group from PG is favored at the binding site. In the closed form of STOmpACTD and in the structure of BbOmpACTD, a sulfate group from the crystallization buffer is tightly bound at the equivalent site. The differences between the closed and open forms of STOmpACTD, suggest a large conformational change that includes an extension of 3 helix by ordering a part of 2-3 loop. We suggest that the sulfate anion observed in these structures mimics the carboxylate group of PG when bound to STOmpACTD. In addition, the binding of PG or a ligand mimic may enhance dimerization of STOmpACTD, or possibly that of full length STOmpA.« less
  • No abstract prepared.
  • No abstract prepared.