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Molecular Insights into α-Synuclein and Its N-terminal Peptides at the Membrane Interface



Candace M. Pfefferkorn, Frank Heinrich, Alexander J. Sodt, Alexander S. Malstev, Richard W. Pastor, Jennifer C. Lee


The role of phospholipids in modulating α-synuclein (α-syn) conformation is of great interest because α-syn aggregation is linked to Parkinson¿s disease. Using a sparsely tethered-bilayer composed of 1:1 molar ratio of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphate (POPA) and 1-palmitoyl-2-oleoyl-snglycero- 3-phosphocholine (POPC) and neutron reflectometry, we determined that α-syn associates with the membrane at both the head group and hydrocarbon chain region, extends into the bulk solvent, and induces membrane thinning (1.44 Å). At the residue level, steady-state fluorescence, time-resolved anisotropy, and proton chemical shifts of single Trp-containing (W4) N-terminal peptides (residues: 1 ¿ 4 (P4), 1 ¿ 6 (P6), 1 ¿ 10 (P10), and 1 ¿ 15 (P15)) were measured in the presence of POPA:POPC vesicles. Calculated apparent membrane partition constants ( app p K ) are highly sequence dependent (P15 > P10 > P6 >> P4) with the first fifteen residues (MDVWMKGLSKAKEGV) nearly recapitulating properties ( app p K ≅ 3600 M¿1) of the full length protein (140 residues, app p K ≅ 4100 M¿1). Though P4, P6, and P10 associate with vesicles, circular dichroism data show that the presence of the amphipathic repeat sequence (KAKEGV) in P15 is important for the formation of α-helical structure. Fluorescence measurments using brominated lipids as heavy-atom quenchers reveal that W4 in P6, P10, P15, and the full length protein interact with the hydrocarbon chain region at depths of approximately 6 to 11 Å above the bilayer center. Consistent results were obtained by molecular dynamics simulations of bilayer-bound P15, where W4 resides in a broad free energy minimum, 5.5 ¿ 11.5 Å above the bilayer center.
Biophysical Journal


tryptophan, fluorescence, neutron reflectometry, nuclear magnetic resonance, all-atom simulation


Pfefferkorn, C. , Heinrich, F. , Sodt, A. , Malstev, A. , Pastor, R. and Lee, J. (2012), Molecular Insights into α-Synuclein and Its N-terminal Peptides at the Membrane Interface, Biophysical Journal, [online], (Accessed July 18, 2024)


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Created January 31, 2012, Updated October 12, 2021