Abstract
Binding of human α-Synuclein, a protein associated with Parkinson’s disease, to natural membranes is thought to be crucial in relation to its pathological and physiological function. Here the binding of αS to small unilamellar vesicles mimicking the inner mitochondrial and the neuronal plasma membrane is studied in situ by continuous wave and pulsed electron paramagnetic resonance. Local binding information of αS spin labeled by MTSL at positions 56 and 69 respectively shows that also helix 2 (residues 50–100) binds firmly to both membranes. By double electron-electron resonance (DEER) on the mutant spin labeled at positions 27 and 56 (αS 27/56) a new conformation on the membrane is found with a distance of 3.6 nm/ 3.7 nm between residues 27 and 56. In view of the low negative charge density of these membranes, the strong interaction is surprising, emphasizing that function and pathology of αS could involve synaptic vesicles and mitochondria.
Highlights
Parkinson’s disease [1] is the second most prevalent neurodegenerative disorder [2], characterized by the formation of intra-neuronal protein deposits such as Lewy bodies [3] [4]
We focus on two membranes [35]: a. the inner mitochondrial membrane (IMM) and b. the neuronal plasma membrane (NPM), presented in the form of small unilamellar vesicles (SUVs)
The double electron-electron resonance (DEER) time traces were analyzed by Tikhonov regularization and the resulting distance distributions are shown in Fig 2C and Fig 2D
Summary
Parkinson’s disease [1] is the second most prevalent neurodegenerative disorder [2], characterized by the formation of intra-neuronal protein deposits such as Lewy bodies [3] [4]. Its physiological function is still not clear, it has been implicated in neurotransmitter release [9] [10] and vesicle trafficking [11]. Both these functions involve the neuronal plasma membrane (NPM). The protein αS is associated with diseases like dementia, and mitochondrial dysfunction [12] [13] and with aging [14]. The protein occurs in mitochondria, especially close to the inner mitochondrial membrane[16][17] and it is thought to be associated with mitochondrial damage [18] [19]
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