Two-Dimensional Crowding Uncovers a Hidden Conformation of ?-Synuclein.

ABSTRACT: The intrinsically disordered protein (IDP), ?-synuclein (?S), is well-known for phospholipid membrane binding-coupled folding into tunable helical conformers. Here, using single-molecule experiments in conjunction with ensemble assays and a theoretical model, we present a unique case demonstrating that the interaction-folding landscape of ?S can be tuned by two-dimensional (2D) crowding through simultaneous binding of a second protein on the bilayer surface. Unexpectedly, the experimental data show a clear deviation from a simple competitive inhibition model, but are consistent with a bimodal inhibition mechanism wherein membrane binding of a second protein (a membrane interacting chaperone, Hsp27, in this case) differentially inhibits two distinct modules of ?S-membrane interaction. As a consequence, ?S molecules are forced to access a hidden conformational state on the phospholipid bilayer in which only the higher-affinity module remains membrane-bound. Our results demonstrate that macromolecular crowding in two dimensions can play a significant role in shaping the conformational landscape of membrane-binding IDPs with multiple binding modes.

SUBMITTER: Banerjee PR 

PROVIDER: S-EPMC5166577 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature