Mechanistic insights into Alpha-Synuclein binding to P2RX7: A molecular dynamic and docking study

Area of Science:

• Neuroscience
• Molecular Biology
• Biochemistry

Background:

• Alpha-synucleinopathies (e.g., Parkinson's disease) involve alpha-synuclein (αSyn) aggregation.
• P2RX7 receptor activation by extracellular ATP is linked to inflammation and neuronal degeneration.
• αSyn binding to P2RX7 is proposed to cause pore dilation and exacerbate inflammation.

Purpose of the Study:

• To elucidate the molecular mechanisms and binding sites of the P2RX7-αSyn interaction.
• To understand how αSyn binding affects P2RX7's structural and functional dynamics.
• To identify key residues involved in the P2RX7-αSyn interaction for potential therapeutic targets.

Main Methods:

• Data curation, molecular docking using six tools, and microsecond all-atom molecular dynamics (MD) simulations.
• Analysis of cryo-electron microscopy (cryo-EM) structures of P2RX7.
• Secondary structure analysis, contact-based and solvent accessibility analyses, and protein structure network (PSN) studies.

Main Results:

• αSyn interactomes are primarily linked to mitochondrial functions, while P2RX7 interactors involve receptor internalization and calcium transport.
• Molecular docking identified preferential binding of αSyn's N-terminal domain (NTD) to P2RX7's transmembrane domain.
• MD simulations revealed significant atomic fluctuations and unfolding in P2RX7 regions associated with pore dilation and desensitization, identifying crucial interacting residues.

Conclusions:

• This study elucidates the molecular basis of P2RX7-αSyn interaction, highlighting the role of αSyn-NTD binding.
• The findings reveal how αSyn binding induces structural changes in P2RX7, potentially driving neurodegeneration.
• Understanding these interactions provides insights for developing therapeutic strategies against αSyn-related neurodegenerative diseases.