Abstract:
:A random coil-helix transition underlies the association of the presynaptic protein α-synuclein (αS) with curved vesicle membranes to fold Asp2-Ala89 into a continuous helix. To clarify this transition, we examined αS folding cooperativity, helix nucleation and propagation in relation to membrane stabilization and leakage on diverse small unilamellar vesicles. The sequences centering on Phe4 and Tyr39 initiate lipid interactions and the Phe4 region nucleates the helix irrespective of the order of Ser9-Ala89. However, helix propagation is not the sum of individual αS-membrane interactions; it requires non-uniform but balanced sequence distributions of lipid affinities and helix flexibility. The attained helix propagation, like folding cooperativity, depends distinctly on membrane lipid composition and correlates to the degree of αS-conferred membrane stabilization. Contrary to classical coil-helix folding thermodynamics, helix propagation proceeds with a small gain in free energy relative to helix nucleation indicating that its binding enthalpy is expended to compensate a high entropic cost of reducing lipid-packing defects in the curved membrane. Non-saturating lipid conditions or rigidification of the αS helix triggers an increase in small unilamellar vesicle membrane leakage. Thus, αS folding parameters appear highly optimized and closely matched to stabilize and protect its target membrane. Aging-associated changes in lipid and αS concentrations may therefore alter synaptic plasticity and contribute to αS misfolding that culminates in fatal neurodegeneration.
journal_name
J Mol Bioljournal_title
Journal of molecular biologyauthors
Lokappa SB,Suk JE,Balasubramanian A,Samanta S,Situ AJ,Ulmer TSdoi
10.1016/j.jmb.2014.02.024subject
Has Abstractpub_date
2014-05-15 00:00:00pages
2130-44issue
10eissn
0022-2836issn
1089-8638pii
S0022-2836(14)00124-7journal_volume
426pub_type
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