Experimental Evidence for Phosphorylation-Driven Allosteric Regulation of Alpha Synuclein Function.

Area of Science:

• Neuroscience
• Biochemistry
• Structural Biology

Background:

• Phosphorylation of alpha synuclein at serine 129 (pS129) is linked to neurodegenerative diseases.
• pS129 is functionally connected to neurotransmitter release and synaptic vesicle (SV) cycling.
• Alpha synuclein binding to VAMP-2 and synapsin requires phosphorylation, suggesting allosteric regulation.

Purpose of the Study:

• To investigate the structural impact of pS129 and oxidized alpha synuclein.
• To understand the allosteric regulation of alpha synuclein protein-protein interactions by pS129.

Main Methods:

• Tandem mass spectrometry was used to study alpha synuclein, pS129, and oxidized forms.
• Techniques included collision-induced unfolding, covalent labeling, and cross-linking.
• These methods assessed protein structure, stability, accessible residues, and residue proximity.

Main Results:

• Phosphorylated-S129 alpha synuclein adopts a more stable and compact conformation.
• Evidence suggests an extensively folded amphipathic region interacting with the VAMP-2 binding domain.
• Oxidized alpha synuclein was also studied.

Conclusions:

• pS129 induces alpha synuclein folding, likely modulating interactions with SVs and membranes.
• This phosphorylation-induced structural change is key to alpha synuclein's function in neurotransmission.
• Findings offer insights into neurodegenerative disease mechanisms.