Membrane proteins require lipid bilayers for function. While lipid compositions reach enormous complexities,high-resolution structures are usually obtained in artificial detergents.T ou nderstand whether and how lipids guide membrane protein function, we use single-molecule FRET to probe the dynamics of DtpA, amember of the proton-coupled oligopeptide transporter (POT) family,i nv arious lipid environments.W es how that detergents trap DtpA in ad ynamic ensemble with cytoplasmic opening. Only reconstitutions in more native environments restore cooperativity,a llowing an opening to the extracellular side and asampling of all relevant states.Bilayer compositions tune the abundance of these states. Anovel state with an extreme cytoplasmic opening is accessible in bilayers with anionic head groups.Hence,chemical diversity of membranes translates into structural diversity,w ith the current POTs tructures only sampling ap ortion of the full structural space.
Specific protein interactions typically require well-shaped binding interfaces. Here, we report a cunning exception. The disordered tail of the cell-adhesion protein E-cadherin dynamically samples a large surface area of the proto-oncogene β-catenin. Single-molecule experiments and molecular simulations resolve these motions with high resolution in space and time. Contacts break and form within hundreds of microseconds without dissociation of the complex. A few persistent interactions provide specificity whereas unspecific contacts boost affinity. The energy landscape of this complex is rugged with many small barriers (3 - 4 kT) and reconciles specificity, high affinity, and extreme disorder. Given the roles of β-catenin in cell-adhesion, signalling, and cancer, this Velcro-like design has the potential to tune the stability of the complex without requiring dissociation.
Intrinsically disordered proteins often form dynamic complexes with their ligands. Yet, the speed and amplitude of these motions are hidden in classical binding kinetics. Here, we directly measure the dynamics in an exceptionally mobile, high-affinity complex. We show that the disordered tail of the cell adhesion protein E-cadherin dynamically samples a large surface area of the protooncogene β-catenin. Single-molecule experiments and molecular simulations resolve these motions with high resolution in space and time. Contacts break and form within hundreds of microseconds without a dissociation of the complex. The energy landscape of this complex is rugged with many small barriers (3 to 4 kBT) and reconciles specificity, high affinity, and extreme disorder. A few persistent contacts provide specificity, whereas unspecific interactions boost affinity.
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