A Proline Switch Explains Kinetic Heterogeneity in a Coupled Folding and Binding Reaction

Franziska Zosel,Davide Mercadante,Daniel Nettels,Benjamin Schuler

doi:10.1016/j.bpj.2018.11.994

Abstract

The interactions of intrinsically disordered proteins (IDPs) with their molecular targets are essential for the regulation of many cellular processes. IDPs can perform their functions while disordered, and they may fold to structured conformations on binding. Here we show that the cis/trans isomerization of peptidyl-prolyl bonds can have a pronounced effect on the interactions of IDPs. By single-molecule spectroscopy, we identify a conserved proline residue in NCBD (the nuclear-coactivator binding domain of CBP) whose cis/trans isomerization in the unbound state modulates the association and dissociation rates with its binding partner, ACTR. As a result, NCBD switches on a time scale of tens of seconds between two populations that differ in their affinities to ACTR by about an order of magnitude. Molecular dynamics simulations indicate as a cause reduced packing of the complex for the cis isomer. Peptidyl-prolyl cis/trans isomerization may be an important previously unidentified mechanism for regulating IDP interactions.

Highlights

887-Plat Functional Adaptation Mutations Alter Propensity for Alpha-Helical Conformation in the Intrinsically Disordered Glucocorticoid Receptor Tau1Core Activation Domain Lennart Nilsson1, Anthony Wright2, Kyou-Hoon Han3. 1Dept Biosci/Nutr, Karolinska Inst, Huddinge, Sweden, 2Dept Lab Medicine, Karolinska Inst, Huddinge, Sweden, 3Dept of Nano and Bioinformatics, University of Science and Technology, Daejeon, Republic of Korea
Linking changes in the amino acid sequence to the evolution of transcription regulatory domains is often complicated by the low sequence complexity and high mutation rates of intrinsically disordered protein regions
Over a third of the eukaryotic proteome consists of intrinsically disordered proteins and regions (IDRs) that either fold upon binding into distinct context-dependent structures or persist in disordered albeit functional states

Summary

Introduction

887-Plat Functional Adaptation Mutations Alter Propensity for Alpha-Helical Conformation in the Intrinsically Disordered Glucocorticoid Receptor Tau1Core Activation Domain Lennart Nilsson1, Anthony Wright2, Kyou-Hoon Han3. 1Dept Biosci/Nutr, Karolinska Inst, Huddinge, Sweden, 2Dept Lab Medicine, Karolinska Inst, Huddinge, Sweden, 3Dept of Nano and Bioinformatics, University of Science and Technology, Daejeon, Republic of Korea. Linking changes in the amino acid sequence to the evolution of transcription regulatory domains is often complicated by the low sequence complexity and high mutation rates of intrinsically disordered protein regions. 884-Plat Conformational Effects of a Disease-Associated Hydrophobic-to-Hydrophobic Substitution and Histidine Protonation State Located at the Midpoint of the Intrinsically Disordered Region of proBDNF Ruchi Lohia, Grace Brannigan.

Results

Conclusion