Physical and Mechanical Properties of Monomeric Alpha-Synuclein Provide Leads to Molecular Function.

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The activity of the intrinsically disordered protein, α-synuclein, in human brain neurons is associated with neurotransmitter storage, trafficking, and release, and its dysfunctional aggregation is linked to Parkinsons's disease. To describe the as-yet unknown molecular function of α-synuclein, we address physical and mechanical properties of the isolated, monomeric human protein, by measuring the protein-coupled solvent dynamics detected by the electron paramagnetic resonance (EPR) spin probe, TEMPOL, colocalized in solvent regions around the protein, under temperature-controlled (200-265 K) ice-boundary confinement. The spin probe rotational correlation time at all temperatures is characterized by two components that are assigned to protein hydration water regions around nominally stable protein structure (slow motion; distal N-terminal and central domains) and to dynamically disordered regions (fast motion; C-terminal and proximal N-terminal domains). The equilibrium change from fast to slow motion components with decreasing temperature represents two sequential compaction processes of the protein. The processes are intervened by a dynamical disorder-to-order transition in the protein hydration solvent, which evidences the formation of stable, tertiary protein structure at a critical level of compaction. A model is presented, in which the dynamical macrostate reported by the spin probe at each temperature-dependent level of confinement is composed of an ensemble of structural microstates with common dynamical properties. The extrapolated room temperature free energy for compaction suggests facile modulation by in vivo confinement levels. The compaction and dynamical properties reveal molecular-mechanistic bases for function of α-synuclein in vivo.

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