Two-Dimensional Crowding Uncovers a Hidden Conformation of α-Synuclein.
Angew Chem Int Ed Engl
; 55(41): 12789-12792, 2016 10 04.
Article
em En
| MEDLINE
| ID: mdl-27612332
ABSTRACT
The intrinsically disordered protein (IDP), α-synuclein (αS), 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 αS 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 αS-membrane interaction. As a consequence, αS 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.
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Base de dados:
MEDLINE
Assunto principal:
Alfa-Sinucleína
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article