TY - JOUR
T1 - Polymer effects modulate binding affinities in disordered proteins
AU - Vancraenenbroeck, Renee
AU - Harel, Yair S.
AU - Zheng, Wenwei
AU - Hofmann, Hagen
N1 - Funding Information:
ACKNOWLEDGMENTS. We enjoyed the critical discussions and helpful comments of many colleagues. Our thanks go to Deborah Fass, David Gruia, Gilad Haran, Amnon Horovitz, Gabriel Rosenblum, Samuel Safran, Benjamin Schuler, Philipp Selenko, and Felix Wiggers. We also thank Zoe Aridor for help in the purification and labeling of the ΔMYC-variant. This research was supported by the Benoziyo Fund for the Advancement of Science, the Car-olito Foundation, The Gurwin Family Fund for Scientific Research, and The Leir Charitable Foundation.
Funding Information:
This research was supported by the Benoziyo Fund for the Advancement of Science, the Carolito Foundation, The Gurwin Family Fund for Scientific Research, and The Leir Charitable Foundation
Publisher Copyright:
© 2019 National Academy of Sciences. All rights reserved.
PY - 2019/9/24
Y1 - 2019/9/24
N2 - Structural disorder is widespread in regulatory protein networks. Weak and transient interactions render disordered proteins particularly sensitive to fluctuations in solution conditions such as ion and crowder concentrations. How this sensitivity alters folding coupled binding reactions, however, has not been fully understood. Here, we demonstrate that salt jointly modulates polymer properties and binding affinities of 5 disordered proteins from a transcription factor network. A combination of single-molecule Förster resonance energy transfer experiments, polymer theory, and molecular simulations shows that all 5 proteins expand with increasing ionic strengths due to Debye-Hückel charge screening. Simultaneously, pairwise affinities between the proteins increase by an order of magnitude within physiological salt limits. A quantitative analysis shows that 50% of the affinity increase can be explained by changes in the disordered state. Disordered state properties therefore have a functional relevance even if these states are not directly involved in biological functions. Numerical solutions of coupled binding equilibria with our results show that networks of homologous disordered proteins can function surprisingly robustly in fluctuating cellular environments, despite the sensitivity of its individual proteins.
AB - Structural disorder is widespread in regulatory protein networks. Weak and transient interactions render disordered proteins particularly sensitive to fluctuations in solution conditions such as ion and crowder concentrations. How this sensitivity alters folding coupled binding reactions, however, has not been fully understood. Here, we demonstrate that salt jointly modulates polymer properties and binding affinities of 5 disordered proteins from a transcription factor network. A combination of single-molecule Förster resonance energy transfer experiments, polymer theory, and molecular simulations shows that all 5 proteins expand with increasing ionic strengths due to Debye-Hückel charge screening. Simultaneously, pairwise affinities between the proteins increase by an order of magnitude within physiological salt limits. A quantitative analysis shows that 50% of the affinity increase can be explained by changes in the disordered state. Disordered state properties therefore have a functional relevance even if these states are not directly involved in biological functions. Numerical solutions of coupled binding equilibria with our results show that networks of homologous disordered proteins can function surprisingly robustly in fluctuating cellular environments, despite the sensitivity of its individual proteins.
KW - Collapse
KW - Intrinsically disordered protein
KW - Protein folding
KW - Protein network
KW - Single-molecule FRET
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U2 - 10.1073/pnas.1904997116
DO - 10.1073/pnas.1904997116
M3 - Article
C2 - 31488718
AN - SCOPUS:85072633049
SN - 0027-8424
VL - 116
SP - 19506
EP - 19512
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 39
ER -