Structural Dynamics and Catalytic Mechanism of ATP13A2 (PARK9) from Simulations

Area of Science:

• Biochemistry
• Structural Biology
• Neuroscience

Background:

• ATP13A2, a PARK gene, is linked to Parkinson's disease (PD) but its 3D structure and catalytic mechanism remain uncharacterized.
• Understanding ATP13A2's function is vital for elucidating PD pathogenesis and developing therapeutic strategies.

Purpose of the Study:

• To model the three-dimensional structure and catalytic mechanism of the full-length ATP13A2 protein in its E1-ATP state.
• To investigate the role of magnesium ions and key catalytic residues in ATP hydrolysis by ATP13A2.

Main Methods:

• Molecular dynamics (MD) simulations to observe protein behavior and ion interactions.
• Quantum cluster and quantum mechanical/molecular mechanical (QM/MM) methods to calculate reaction profiles and barrier heights for ATP cleavage.
• Analysis of conserved residues (Arg686, Lys859) and their impact on catalytic activity.

Main Results:

• MD simulations identified two Mg2+ cations stabilizing ATP binding at the active site.
• QM/MM calculations revealed significantly reduced activation energy for ATP cleavage with two Mg2+ ions (7.5 kcal mol-1) compared to one (12.5 kcal mol-1).
• The catalytic residue Arg686 was found to substantially lower the ATP cleavage barrier, while Lys859 stabilizes the reactant state.

Conclusions:

• The study elucidates the catalytically competent ATP conformation and the role of Mg2+ cofactors in ATP13A2 function.
• Key residues, particularly Arg686, play a critical role in modulating the reaction barrier height, with mutations potentially disrupting enzymatic activity and contributing to PD.
• Identified large binding pockets, including a transmembrane domain pocket, suggest potential sites for ATP13A2 cargo binding and transport.