Biophysics of α-synuclein membrane interactions

Abstract

Membrane proteins participate in nearly all cellular processes; however, because of experimental limitations, their characterization lags far behind that of soluble proteins. Peripheral membrane proteins are particularly challenging to study because of their inherent propensity to adopt multiple and/or transient conformations in solution and upon membrane association. In this review, we summarize useful biophysical techniques for the study of peripheral membrane proteins and their application in the characterization of the membrane interactions of the natively unfolded and Parkinson's disease (PD) related protein, α-synuclein (α-syn). We give particular focus to studies that have led to the current understanding of membrane-bound α-syn structure and the elucidation of specific membrane properties that affect α-syn-membrane binding. Finally, we discuss biophysical evidence supporting a key role for membranes and α-syn in PD pathogenesis. This article is part of a Special Issue entitled: Membrane protein structure and function.

Fig. 1

Selected biophysical techniques used to examine membrane binding proteins such as α-synuclein.

Fig. 2

(Top) α-Synuclein primary amino acid sequence with aromatic (light blue), acidic (red), and lysine (blue) residues highlighted. (Bottom) Schematic representation of α-synuclein with amphipathic repeats, non-amyloid β component (NAC) region, membrane binding domain, and acidic region in blue, light blue, gray, and red, respectively. The location of the amphiphatic repeats, the disease-related mutations, and the membrane binding domain also are denoted.

Fig. 3

Lipid and membrane mimic structure. (A) Chemical structure of the glycerol phospholipid and sphingolipid backbone with different headgroups (X) and their corresponding names indicated. The R1, R2, and R designate fatty acid chains. (B) Schematic of the approximate size and organization of membrane mimics commonly used in biophysical research. Corresponding cellular compartments are provided for relative size reference.

Fig. 4

Side and top view of micelle-bound α-synuclein (PDB ID: 1XQ8). The membrane binding domain (gray), non-amyloid β component region, and acidic region are colored in gray, light blue, and red, respectively. Lysine residues found within the amphipathic repeats are shown.