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Title: Redox-sensitive structural change in the A-domain of HMGB1 and its implication for the binding to cisplatin modified DNA

Highlights: •The structure of the oxidized A-domain of human HMGB1 was solved. •Phe38 ring was flipped in the oxidized structure from that in the reduced form. •The flipped ring disables the intercalation into the cisplatinated lesions. •The functionally relevant redox-dependent structural change was described. -- Abstract: HMGB1 (high-mobility group B1) is a ubiquitously expressed bifunctional protein that acts as a nuclear protein in cells and also as an inflammatory mediator in the extracellular space. HMGB1 changes its functions according to the redox states in both intra- and extra-cellular environments. Two cysteines, Cys23 and Cys45, in the A-domain of HMGB1 form a disulfide bond under oxidative conditions. The A-domain with the disulfide bond shows reduced affinity to cisplatin modified DNA. We have solved the oxidized A-domain structure by NMR. In the structure, Phe38 has a flipped ring orientation from that found in the reduced form; the phenyl ring in the reduced form intercalates into the platinated lesion in DNA. The phenyl ring orientation in the oxidized form is stabilized through intramolecular hydrophobic contacts. The reorientation of the Phe38 ring by the disulfide bond in the A-domain may explain the reduced HMGB1 binding affinity towards cisplatinated DNA.
Authors:
 [1] ;  [2] ;  [1] ;  [1] ;  [3] ;  [4] ;  [1] ;  [3]
  1. Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Kagamiyama 1-3-1, Higashi-Hiroshima 739-8526 (Japan)
  2. Research Center for the Mathematics on Chromatin Live Dynamics (RcMcD), Graduate School of Science, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima 739-8526 (Japan)
  3. (RcMcD), Graduate School of Science, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima 739-8526 (Japan)
  4. Protein Research Institute, Osaka University, 3-2 Yamadaoka, Suita 565-0871 (Japan)
Publication Date:
OSTI Identifier:
22242202
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 441; Journal Issue: 4; Other Information: Copyright (c) 2013 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; CLATHRATES; CYSTEINE; DISULFIDES; DNA; DOMAIN STRUCTURE; EXTRACELLULAR SPACE; INFLAMMATION; NUCLEAR MAGNETIC RESONANCE; OXIDATION; PROTEINS