Alpha Synuclein: Structure

α-synuclein is a 140-amino acid protein that contains a sequence motif unique to the synuclein family (Murray et al., 2003). The protein has three different domains: 1) an N terminal, 2) C terminal, and 3) middle NAC domain. The N terminal region contains all the mutations associated with PD, and consists of conserved residue repeats (KTK(E/Q)GV) that form amphipathic alpha helixes. The size of the repeats, along with their lipid binding ability enables the peptide to form three helical tu­­rns and directly contact the membrane. The polar C terminus is defined by an abundance of three residues (proline, aspartate, and glutamate) (Dehay et al., 2015) and is less conserved than the N terminus (Bendor et al., 2013). A C terminal deletion causes increased α-synuclein aggregation, which suggests that this domain regulates protein accumulation (Murray et al., 2003). Finally, the NAC domain contains many hydrophobic amino acids that are key in α-synuclein aggregation (Dehay et al., 2015).

There is conflicting research on α-synuclein’s native structure; originally the protein was described as unfolded, but recent discoveries have suggested that it remains folded in a solution. For example, Wang et al. (2011) described α-synuclein as a stable helically folded tetramer without lipid bilayers or micelles. The most plausible explanation for the findings of multiple conformations of α-synuclein is that the protein exists in many oligomeric states in a dynamic equilibrium (Dehay et al., 2015).