期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2021
卷号：118
期号：37
DOI：10.1073/pnas.2106690118
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Flexibility in complexes between intrinsically disordered proteins and folded ligands is widespread in nature. However, timescales and spatial amplitudes of such dynamics remained unexplored for most systems. Our results show that the disordered cytoplasmic tail of the cell adhesion protein E-cadherin diffuses across the entire surface of its folded binding partner β-catenin at fast submillisecond timescales. The nanometer amplitude of these motions could allow kinases to access their recognition motifs without requiring a dissociation of the complex. We expect that the rugged energy landscape found in the E-cadherin/β-catenin complex is a defining feature of dynamic and partially disordered protein complexes.
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
k
B
T) and reconciles specificity, high affinity, and extreme disorder. A few persistent contacts provide specificity, whereas unspecific interactions boost affinity.
