The Cellular Environment Affects Monomeric α-Synuclein Structure

aSyn is a highly dynamic, intrinsically disordered protein that populates an ensemble of different conformations in its functional, monomeric form. Functional, monomeric aSyn structure is stabilised by transient electrostatic and hydrophobic tertiary long-range interactions. Post-translational modifications (PTMs), truncation, and the local cellular environment, such as pH and ion content, can influence monomeric aSyn structure. A disruption of monomeric aSyn structure can bias the protein population towards aggregation-prone conformations, leading to the formation of amyloid fibrils. The structure of monomeric aSyn can imprint into fibril morphology and lead to the formation of different aSyn strains. Different aSyn fibril strains have been shown to lead to different levels of toxicity and may influence pathophysiology. The presynaptic protein α-synuclein (aSyn) is an ‘intrinsically disordered protein’ that is highly dynamic in conformation. Transient intramolecular interactions between its charged N and C termini, and between its hydrophobic region and the C terminus, prevent self-association. These interactions inhibit the formation of insoluble inclusions, which are the pathological hallmark of Parkinson’s disease and many other synucleinopathies. This review discusses how these intramolecular interactions are influenced by the specific environment aSyn is in. We discuss how charge, pH, calcium, and salt affect the physiological structure of monomeric aSyn, and how they may favour the formation of toxic structures. The more we understand the dynamic conformations of aSyn, the better we can design desperately needed therapeutics to prevent disease progression. The presynaptic protein α-synuclein (aSyn) is an ‘intrinsically disordered protein’ that is highly dynamic in conformation. Transient intramolecular interactions between its charged N and C termini, and between its hydrophobic region and the C terminus, prevent self-association. These interactions inhibit the formation of insoluble inclusions, which are the pathological hallmark of Parkinson’s disease and many other synucleinopathies. This review discusses how these intramolecular interactions are influenced by the specific environment aSyn is in. We discuss how charge, pH, calcium, and salt affect the physiological structure of monomeric aSyn, and how they may favour the formation of toxic structures. The more we understand the dynamic conformations of aSyn, the better we can design desperately needed therapeutics to prevent disease progression. microscopy which employs a flexible cantilevered tip that scans the surface of a sample. The deflection of the cantilever is recorded as it scans the sample and translated into an image of the sample topography. a type of dementia that involves extensive deposits of α-synuclein in neurons (see Lewy bodies). It is characterised by changes in movement, behaviour, and cognition. cells providing the main source of the neurotransmitter dopamine in the central nervous system. hydrogen–deuterium exchange mass spectrometry. Mass spectrometry that is based on hydrogen–deuterium exchange and gives information on protein submolecular structure and dynamics. heteronuclear single quantum coherence nuclear magnetic resonance. When applied to an isotope-labelled protein, the coupling of hydrogen and the nitrogen isotope 15N is detected. The coupling is used to probe the chemical shift of each amide, thus providing information on the protein structure. proteins that lack a specific 3D structure. Usual protein characteristics include a high net charge and low hydropathy. abnormal aggregates of proteins detected in neuronal cells in patients with Parkinson’s disease, Lewy body dementia, multiple systems atrophy, and other diseases. a neurodegenerative disorder characterised by Parkinson-like motor symptoms. It is caused by progressive degeneration of neurons in several parts of the brain. the central, hydrophobic region of aSyn (aar 61–94). It was originally found in an amyloid-enriched fraction of Alzheimer’s disease plaques. a neurodegenerative disease that mainly affects the motor system. The characteristic motor symptoms are symptomatic tremors, posture instability, and bradykinesia; these are the first to manifest and are followed by dementia and sensory difficulties. The cause of Parkinson’s disease has not been elucidated, but α-synuclein has been strongly implicated. in the case of aSyn, the most common PTMs are nitration, ubiquitination, and phosphorylation. paramagnetic relaxation enhancement nuclear magnetic resonance. In this NMR technique paramagnetic ions (spin labels) are added to a protein of interest and cause enhanced relaxation of the spins in proximity of the paramagnetic spin label. Studies of IDPs frequently use the label MSTL, which can be targeted to specific cysteine residues introduced through mutation. Provides long-range structural information, up to 25 Å compared with 6 Å using nuclear Overhauser effect. residual dipolar coupling nuclear magnetic resonance. Provides orientation information of magnetic dipole–dipole interactions and gives information on long-range interactions and the global folding of the protein or protein complex. SNAP [soluble NSF(N-ethylmaleimide-sensitive factor) attachment protein] receptor. A group of proteins that mediate vesicle fusion. the substantia nigra is a basal ganglia area in the midbrain, associated with motor skills, learning, and addiction. The pars compacta is a portion of the substantia nigra. Parkinson's disease is characterised by the death of dopaminergic neurons in this region. a technique used for determining the atomic and molecular structure of a crystal using the diffraction of X-rays. In the case of protein samples, it provides 3D structural information at near atomic resolution.