Journal
ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY
Volume 69, Issue -, Pages 669-680Publisher
INT UNION CRYSTALLOGRAPHY
DOI: 10.1107/S0907444913001194
Keywords
oxidative modification; disulfides; sulfonic acid; conformational change; hydrogen; deuterium exchange; mass spectrometry
Funding
- Basic Science Research Program through the National Research Foundation of Korea [2011-0005538]
- National Core Research Center program through the National Research Foundation of Korea [2012-0000952]
- Korean Government (MEST)
- Global Research Lab Program [2012045441]
- Proteogenomics Research Program through the National Research Foundation of Korea [2012036680]
- Ewha Womans University
- Brain Korea 21 (BK21) Project
- National Research Foundation of Korea [2012K1A1A2045441, 2012M3A9B9036679, R31-2012-000-10010-0] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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Nm23-H1/NDPK-A, a tumour metastasis suppressor, is a multifunctional housekeeping enzyme with nucleoside diphosphate kinase activity. Hexameric Nm23-H1 is required for suppression of tumour metastasis and it is dissociated into dimers under oxidative conditions. Here, the crystal structure of oxidized Nm23-H1 is presented. It reveals the formation of an intramolecular disulfide bond between Cys4 and Cys145 that triggers a large conformational change that destabilizes the hexameric state. The dependence of the dissociation dynamics on the H2O2 concentration was determined using hydrogen/deuterium-exchange experiments. The quaternary conformational change provides a suitable environment for the oxidation of Cys109 to sulfonic acid, as demonstrated by peptide sequencing using nanoUPLC-ESI-q-TOF tandem MS. From these and other data, it is proposed that the molecular and cellular functions of Nm23-H1 are regulated by a series of oxidative modifications coupled to its oligomeric states and that the modified cysteines are resolvable by NADPH-dependent reduction systems. These findings broaden the understanding of the complicated enzyme-regulatory mechanisms that operate under oxidative conditions.
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