Structural Insights into Interaction between Mammalian Methionine Sulfoxide Reductase B1 and Thioredoxin

Olena Dobrovolska,Konstantin Shabalin,Alexander Dikiy,Alexander Schmidt,Alexander Yakimov,Elena Shumilina,Georgy Rychkov,Kirill Nerinovski

doi:10.1155/2012/586539

Abstract

Maintenance of the cellular redox balance has vital importance for correcting organism functioning. Methionine sulfoxide reductases (Msrs) are among the key members of the cellular antioxidant defence system. To work properly, methionine sulfoxide reductases need to be reduced by their biological partner, thioredoxin (Trx). This process, according to the available kinetic data, represents the slowest step in the Msrs catalytic cycle. In the present paper, we investigated structural aspects of the intermolecular complex formation between mammalian MsrB1 and Trx. NMR spectroscopy and biocomputing were the two mostly used through the research approaches. The formation of NMR detectable MsrB1/Trx complex was monitored and studied in attempt to understand MsrB1 reduction mechanism. Using NMR data, molecular mechanics, protein docking, and molecular dynamics simulations, it was found that intermediate MsrB1/Trx complex is stabilized by interprotein β-layer. The complex formation accompanied by distortion of disulfide bond within MsrB1 facilitates the reduction of oxidized MsrB1 as it is evidenced by the obtained data.

Highlights

Oxygen is vital for all aerobic biological processes
Using NMR data, molecular mechanics, protein docking, and molecular dynamics simulations, it was found that intermediate MsrB1/Trx complex is stabilized by interprotein β-layer
Methionine residues in proteins are susceptible to oxidation by reactive oxygen and nitrogen species leading to formation of methionine sulfoxide (MetSO)

Summary

Introduction

Oxygen is vital for all aerobic biological processes. about 5% of it is converted into reactive oxygen species (ROS) [1]. Methionine residues in proteins are susceptible to oxidation by reactive oxygen and nitrogen species leading to formation of methionine sulfoxide (MetSO). This modification can result in loss of proteins’ function [2]. Methionine sulfoxide reductases (Msrs) are redox repairing enzymes which reduce MetSO back to methionine (Met). A number of published reports describe the role of methionine sulfoxide reductases in antioxidant defence and the regulation of protein function [6,7,8,9,10]. Methionine sulfoxide reductases reduce both free and protein-bound MetSO, back to Met in the presence of thioredoxin (Trx). Two distinct families constitute Msrs: MsrA, which reduces Sepimer, and MsrB, which is stereospecific for R-epimer of methionine sulfoxide [11,12,13,14]

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Results

Conclusion