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NMR solution structure of human sulfiredoxin (hSrx) and structural basis for the reduction of cysteine‐sulfinic acid
Author(s) -
Lee DuckYeon,
Gruschus James M
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a508-c
Subject(s) - cysteine , chemistry , biochemistry , peroxiredoxin , cysteine metabolism , sulfinic acid , active site , amino acid , enzyme , organic chemistry , peroxidase
ROS Reactive oxygen species (ROS) are generated along with many cellular metabolisms as by‐products. These ROS can oxidize cysteine‐thiol in proteins and that regulate their function. Sulfiredoxin (Srx) is a protein responsible for the reduction of cysteine‐sulfinic acid (‐SO2H) hyperoxidized by H2O2 to cysteine utilizing ATP in eukaryotes. Here we report the NMR solution structure of human Sulfiredoxin (hSrx) with ATP and modeling of the complex with peroxiredoxin (Prx), which is a protein catalyzing the reduction of H2O2. hSrx has a novel structural fold for the ATP hydrolysis activity and is composed of 3 ¥á‐helices and 5β‐sheets. The active site cysteine residue of hSrx is positioned at the N‐terminal of α‐helix and is surrounded by Arg51 and His100, which are well conserved in all Srxs from different species. These may induce a lower pKa of the active site cysteine than that of a free cysteine and stabilize the thiolated form at the physiological pH. Although hSrx has an ATP binding pocket, there is no catalytic acid residue that is conserved in most ATPase and kinase family proteins. As the modeling of the complex‐hyperoxidized Prx (Prx II; 1QMV) and hSrx, Asn 186 of Prx II that complement with Asp187 of Prx I is positioned into the active site of hSrx. By site‐directed mutation and biochemical analysis for mutants, we suggest that Prx I provides a catalytic aspartic acid to stimulate ATP hydrolysis during the reduction of hyperoxidized Prx.