Acta Crystallographica Section D

Biological Crystallography

Volume 69, Part 4 (April 2013)

research papers

Acta Cryst. (2013). D69, 669-680    [ doi:10.1107/S0907444913001194 ]

Structure of Nm23-H1 under oxidative conditions

M.-S. Kim, J. Jeong, J. Jeong, D.-H. Shin and K.-J. Lee

Abstract: 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.

PDB reference: 4eno

Keywords: oxidative modification; disulfides; sulfonic acid; conformational change; hydrogen/deuterium exchange; mass spectrometry.

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[ doi:10.1107/S0907444913001194/mn5019sup1.pdf ]
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