title: Alpha-synuclein populates both elongated and broken helix states on small unilamellar vesicles.
abstract: The misfolding of the protein α-synuclein (αS) has been implicated in the molecular chain of events leading to Parkinson disease. Physiologically, αS undergoes a transition from a random coil to helical conformation upon encountering synaptic vesicle membranes. On analogous small unilamellar vesicles (SUVs), the conformation of αS is dominated by a single elongated αS helix. However, alternative broken helix states have been postulated, mandating experimental clarification. Here, the upper limit for the free energy difference between elongated and broken helix conformations on SUVs resembling synaptic vesicles was determined to be 1.2 ± 0.4 kcal/mol, which amounts to a population ratio of 7.6:1 between both states (12% broken helices). In response to helix breaks at different positions, αS rearranged in an opportunistic manner, thereby minimizing helix abrogations to as little as one to two turns. Enthalpy and entropy measurements of gel state SUV-αS interactions indicated that broken helix states retain the ability to relieve membrane-packing stress. Thus, broken helix states are a distinct physiological feature of the vesicle-bound αS state, making it a "checkered" protein of multiple parallel conformations. A continuous interconversion between structural states may contribute to pathological αS misfolding.
authors.affiliation: Department of Biochemistry and Molecular Biology and Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Sowmya Bekshe
authors.initials: SB
authors.lastname: Lokappa
authors.forename: Tobias S
authors.initials: TS
authors.lastname: Ulmer
mesh_terms: D000595:Amino Acid Sequence; D002151:Calorimetry; D002462:Cell Membrane / Q000378:metabolism; D002942:Circular Dichroism; D003545:Cysteine / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D013696:Temperature; D013816:Thermodynamics; D053835:Unilamellar Liposomes / Q000737:chemistry; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D053835:Unilamellar Liposomes; D051844:alpha-Synuclein; D003545:Cysteine