α-Synuclein and Mitochondria: Probing the Dynamics of Disordered Membrane-protein Regions Using Solid-State Nuclear Magnetic Resonance

JACS Au, Journal Year: 2024, Volume and Issue: 4(6), P. 2372 - 2380

Published: May 28, 2024

The characterization of intrinsically disordered regions (IDRs) in membrane-associated proteins is crucial importance to elucidate key biochemical processes, including cellular signaling, drug targeting, or the role post-translational modifications. These protein pose significant challenges powerful analytical techniques molecular structural investigations. We here applied magic angle spinning solid-state nuclear magnetic resonance quantitatively probe dynamics IDRs membrane-bound α-synuclein (αS), a whose aggregation associated with Parkinson's disease (PD). focused on mitochondrial binding αS, an interaction that has functional and pathological relevance neuronal cells considered for underlying mechanisms PD. Transverse longitudinal 15N relaxation revealed dynamical properties αS bound outer membrane (OMM) are different from those cytosolic state, thus indicating generally not interact fact affected by spatial proximity lipid bilayer. Moreover, changes composition OMM dyshomeostasis PD were found significantly perturb topology state αS. Taken together, our data underline characterizing achieve accurate understanding these elusive play numerous processes occurring surfaces.

Language: Английский

Amyloid-Driven Allostery

Biophysical Chemistry, Journal Year: 2024, Volume and Issue: 315, P. 107320 - 107320

Published: Aug. 30, 2024

The fields of allostery and amyloid-related pathologies, such as Parkinson's disease (PD), have been extensively explored individually, but less is known about how amyloids control allostery. Recent advancements revealed that can drive allosteric effects in both intrinsically disordered proteins, alpha-synuclein (αS), multi-domain signaling protein kinase A (PKA). Amyloid-driven plays a central role explaining the mechanisms gain-of-pathological-function mutations αS (e.g. E46K, which causes early PD onset) loss-of-physiological-function PKA A211D, predisposes to tumors). This review highlights disease-related they cause exposure amyloidogenic regions, leading are either toxic or aberrant signaling. We also discuss multiple potential modulators these effects, MgATP substrates, opening future opportunities improve current pharmacological interventions against PKA-related pathologies. Overall, we show amyloid-driven models useful explain underlying mutations.

Language: Английский