The regulatory domain of CTP: phosphocholine cytidylyltransferase (CCT): structure, membrane interactions, and similarity to α-synuclein.

α-Synuclein, a synaptic vesicle protein whose mis-folding is linked to Parkinson’s Disease, and CTP:phosphocholine cytidylyltransferase (CCT), a key regulatory enzyme in phosphatidylcholine synthesis, share a common structure and function. Both contain lipid-inducible, amphipathic helical (AH) membrane binding motifs followed by unstructured acidic tails. Circular dichroism and tryptophan fluorescence studies comparing membrane-binding properties showed that α-synuclein has weaker affinity for anionic phospholipids than CCT tail regions, and a more stringent lipid compositional selectivity for binding. This may reflect the lower propensity of α-synuclein for helical conformation. However, both proteins can penetrate the lipid bilayer to a similar depth. A phospho-mimic version of the CCT-tail had lower α-helicity than wildtype CCT upon membrane binding, suggesting phosphorylation affects the secondary structure of the adjacent AH domain. These studies provide a foundation for exploring the usefulness of CCT-tails to promote the α-helical character of α-synuclein, thus promoting its non-toxic folding pathway.