FC0080
α-Synuclein  -  Membrane (DOPE-DOPS-DOPC)

Biological function
α-synuclein (αS) is a protein involved in neurotransmitter release in presynaptic terminals, and whose aberrant aggregation is associated with Parkinson’s disease. In dopaminergic neurons, αS exists in a tightly regulated equilibrium between water- soluble and membrane-associated forms. Structural plasticity and the dynamical nature of the membrane-bound state of αS, whose structural properties can sometimes be perturbed even by relatively minor external factors.

Domain organization/sequence features
αS has three regions, which possess distinct structural and dynamical properties, including an N-terminal helical segment having a role of membrane- anchor, an unstructured C-terminal region that is weakly associated with the membrane, and a central region acting as a sensor of the lipid properties and determining the affinity of αS membrane binding.

Structural evidence
The resulting assignments (MAS INEPT resonances) correspond to the region 97-140 and indicate that this fragment adopts unstructured conformations in the membrane-bound state. PRE experiments that the C-terminal domain (residues 99-140), which has been reported to be highly unstructured and extremely flexible, experiences weak and transient interactions with the membrane surface. The central segment of the protein (residues 26-97), which can be described as a membrane-sensor region, has intermediate dynamical properties. This region is indeed too flexible to be detected by cross- polarization experiments but too rigid to be seen by INEPT-type transfer experiments. Based on EPR measurements and transferred NOE data, that this membrane-sensor region adopts α-helical structure when transiently bound to a lipid membrane surface.

Mechanism category
tethering

Significance
Dynamic interactions of the fuzzy C-terminal domain can be used to fine-tune affinity for the membrane via a variety of molecular factors.