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 DJ1 prevents the formation of a functional DJ1 dimer 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 (BAG1 is colored darkmagenta, DJ1 is in green; white surfaces represent interaction regions on BAG-1 and cyan surfaces represent interaction regions on DJ1) restored disrupted alpha helix structures and H-bonds stabilizing the functional site Cys106 (Alpha Helices,  Beta Strands , Turns). The His126-Pro184 H-bond critical to maintaining dimer interfaces was also restored and led to the restoration of dimer formation.

Wild-type DJ1 monomer is colored yellow, mutant L166P DJ1 monomer repaired by BAG-1 at pose 2 is in green, monomer A and monomer B of DJ1 dimer crystal structure (PDB: 2r1t) are colored magenta and salmon, respectively. 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 0.74 Å. The insights into the molecular functions of BAG1 might be applied to further the search for an effective Parkinson’s disease treatment.