Journal:JBSD:13

Mechanism of BAG1 repair on Parkinson’s disease-linked DJ1 mutation

Calvin Yu-Chian Chen ^[1]

Molecular Tour
The L166P mutation of prevents the formation of a and is linked to early-onset Parkinson’s disease (PD). Studies have shown that the chaperon modulator, BCL2-associated athanogene (BAG1) can repair DJ1 mutant thereby restoring its dimer forming function. Molecular simulation techniques were used to elucidate mechanisms underlying the repair of DJ1 L166P by BAG1.

Due to the lack of BAG1 crystal structures, a modeled BAG1 structure was built with I-TASSER using the UniProt peptide sequence (ID: Q99933). The DJ1 L166P mutant model was built and energetically minimized using Build Mutants from Discovery Studio 2.5 (DS 2.5; Accelrys Inc., San Diego, CA), with reference to DJ1 monomer (PDB: 1PDV). A dock-based dimerization simulation showed that interaction between mutant DJ1 and BAG1 at pose 2 restored disrupted alpha helix structures and H-bonds stabilizing the functional site Cys106. The His126-Pro184 H-bond critical to maintaining dimer interfaces was also restored and led to the restoration of dimer formation. RMSD comparisons indicated that Pose 2-DJ1 dimer was extremely similar to that of the crystal DJ1 dimer structure (PDB: 2R1T) with an RMSD of 0.74ֵ. The insights into the molecular functions of BAG1 might be applied to further the search for an effective Parkinson’s disease treatment.