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).