The structural analysis of the pro-oxidant copper-binding site of denatured apo-H43R SOD1 and the elucidation of the origin of the acquisition of the pro-oxidant activity

Nobuhiro Fujimaki, Takashi Miura, Takakazu Nakabayashi

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

The pathogenesis of amyotrophic lateral sclerosis (ALS) is associated with mutations of Cu,Zn-superoxide dismutase (SOD1), which is a representative antioxidant enzyme. A previous study showed that the denatured apo-form of an ALS-linked mutant of human SOD1, His43 → Arg (H43R), obtains pro-oxidant activity as the reverse behavior of the native antioxidant activity by rebinding Cu2+, which is considered to be closely related to the development of ALS. The Cu2+-binding site in denatured apo-H43R can be regarded as the center of the pro-oxidant activity, causing cellular oxidative stress. In the present study, the structure of the Cu2+-binding site of denatured apo-H43R was investigated to clarify the mechanism of the acquisition of the pro-oxidant activity. His residues constructing the Cu2+-binding site in denatured apo-H43R were experimentally assigned by absorption and fluorescence-based assays of SOD1 mutants, in which each of the seven His residues in H43R SOD1 is replaced with Ala. It was found that His120 is not involved with the Cu2+-binding site after denaturation, although the other His residues constructing the metal-binding site remain constant after denaturation. The disappearance of His120 from the Cu2+-binding site is therefore considered to be one of the important factors in obtaining the pro-oxidant activity. The mechanism of the acquisition of the pro-oxidant activity is discussed based on the results obtained.

Original languageEnglish
Pages (from-to)4468-4475
Number of pages8
JournalPhysical Chemistry Chemical Physics
Volume18
Issue number6
DOIs
Publication statusPublished - 2016 Jan 1

ASJC Scopus subject areas

  • Physics and Astronomy(all)
  • Physical and Theoretical Chemistry

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