Structural features of human DJ-1 in distinct Cys106 oxidative states and their relevance to its loss of function in disease

Publication date: Available online 24 August 2017
Source:Biochimica et Biophysica Acta (BBA) - General Subjects
Author(s): Róbert Kiss, Max Zhu, Balázs Jójárt, András Czajlik, Katalin Solti, Balázs Fórizs, Éva Nagy, Ferenc Zsila, Tamás Beke-Somfai, Gergely Tóth
DJ-1 (PARK7) is a multifunctional protein linked to the onset and progression of a number of diseases, most of which are associated with high oxidative stress. The oxidation state of Cys106 of DJ-1 is believed to determine the specific functions of the protein in normal and disease conditions. Here we report molecular dynamics simulation and biophysical experimental studies on DJ-1 in reduced (Cys106, S), oxidized (Cys106, −SO2⁻), and over-oxidized (Cys106, −SO3⁻) states. To simulate the different oxidation states of Cys106 in DJ-1, AMBER related force field parameters were developed and reported for 3-sulfinoalanine and cysteine sulfonic acid. Our studies found that the overall structure of DJ-1 in different oxidation states was similar globally, while it differed locally significantly, which have implications on its stability, function and its link to disease on-set. Importantly, the results suggest that over-oxidation may trigger loss of functions due to local structural modification in the Cys106 containing pocket of DJ-1 and structurally destabilize the dimeric state of DJ-1, which is believed to be its bioactive conformation. Such loss of functions would result in reduced ability of DJ-1 to protect from oxidative stress insults and may lead to increased progression of disease.



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