Role of Intrinsically Disordered Regions in Acceleration of Protein–Protein Association
Abstract
Although intrinsically disordered proteins and intrinsically disordered regions (IDRs) in folded proteins are not able to form stable structures, it is known that they play critically important roles in various biological processes. However, despite multiple studies, the molecular mechanisms of their functions remain not fully understood. In this work, we theoretically investigate the role of IDRs in acceleration of protein-protein association processes. Our hypothesis is that, in protein pairs with several independent binding sites, the association process goes faster if some of these binding sites are located on IDRs or connected by IDRs. To test this idea, we employed analytical modeling, numerical calculations, and Brownian dynamics computer simulations to calculate protein-protein association reaction rates for the ERK2-EtsΔ138 system, belonging to the RAS-RAF-MEK-ERK signaling pathway in living cells. It is found that putting a binding site on IDR accelerates the association process by a factor of 3 to 4. Possible molecular explanations for these observations are presented, and other systems that might use this mechanism are also mentioned.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
When protein interaction sites are located within intrinsically disordered regions, the protein associations required to propagate cell signaling pathways are significantly accelerated.
“When protein interaction sites are located within intrinsically disordered regions, the protein associations required to propagate cell signaling pathways are significantly accelerated [29].”
From Intrinsically disordered proteins play diverse roles in cell signaling (2022) · cites this paper as [29]
Cites
Abraham, M. J., Murtola, T., Schulz, R., Páll, S., Smith, J. C., Hess, B., & Lindahl, E. (2015) · SoftwareX · doi:10.1016/j.softx.2015.06.001 · Cited by 27,190 · see citing works
GROMACS: A message-passing parallel molecular dynamics implementation
Berendsen, H. J. C., van der Spoel, D., & van Drunen, R. (1995) · Computer Physics Communications · doi:10.1016/0010-4655(95)00042-e · Cited by 10,748 · see citing works
Brownian motion in a field of force and the diffusion model of chemical reactions
Kramers, H. A. (1940) · Physica · doi:10.1016/s0031-8914(40)90098-2 · Cited by 8,561 · see citing works
Reaction-rate theory: fifty years after Kramers
Hänggi, P., Talkner, P., & Borkovec, M. (1990) · Reviews of Modern Physics · doi:10.1103/revmodphys.62.251 · Cited by 6,154 · see citing works
Rubinstein, M., & Colby, R. H. (2003) · doi:10.1093/oso/9780198520597.001.0001 · Cited by 5,686 · see citing works
Lodish, H. F. (1986) · Cited by 5,640 · see citing works
Intrinsically unstructured proteins: re-assessing the protein structure-function paradigm
Wright, P. E., & Dyson, H. J. (1999) · Journal of Molecular Biology · doi:10.1006/jmbi.1999.3110 · Cited by 2,968 · see citing works
Intrinsically disordered proteins in cellular signalling and regulation
Wright, P. E., & Dyson, H. J. (2014) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3920 · Cited by 2,371 · see citing works
Berg, H. C., & Purcell, E. M. (1977) · Biophysical Journal · doi:10.1016/s0006-3495(77)85544-6 · Cited by 1,902 · see citing works
Diffusion-controlled reaction rates
Collins, F. C., & Kimball, G. E. (1949) · Journal of Colloid Science · doi:10.1016/0095-8522(49)90023-9 · Cited by 1,361 · see citing works
Intrinsic Disorder in Cell-signaling and Cancer-associated Proteins
Iakoucheva, L. M., Brown, C. J., Lawson, J. D., Obradović, Z., & Dunker, A. K. (2002) · Journal of Molecular Biology · doi:10.1016/s0022-2836(02)00969-5 · Cited by 1,214 · see citing works
The ETS-domain transcription factor family
Sharrocks, A. D. (2001) · Nature Reviews Molecular Cell Biology · doi:10.1038/35099076 · Cited by 1,086 · see citing works
Bmi-1 collaborates with c-Myc in tumorigenesis by inhibiting c-Myc-induced apoptosis via INK4a/ARFPreprint
Jacobs, J. J. L., Scheijen, B., Voncken, J. W., Kieboom, K., Berns, A. J. M., & van Lohuizen, M. (1999) · Genes & Development · doi:10.1101/gad.13.20.2678 · Cited by 1,060 · see citing works
Intrinsically Disordered Proteins and Intrinsically Disordered Protein Regions
Oldfield, C. J., & Dunker, A. K. (2014) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-072711-164947 · Cited by 1,057 · see citing works
Speeding molecular recognition by using the folding funnel: The fly-casting mechanism
Shoemaker, B. A., Portman, J. J., & Wolynes, P. G. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.160259697 · Cited by 971 · see citing works
A conserved docking motif in MAP kinases common to substrates, activators and regulators
Tanoue, T., Adachi, M., Moriguchi, T., & Nishida, E. (2000) · Nature Cell Biology · doi:10.1038/35000065 · Cited by 816 · see citing works
First passage time approach to diffusion controlled reactions
Szabó, A., Schulten, K. J., & Schulten, Z. (1980) · The Journal of Chemical Physics · doi:10.1063/1.439715 · Cited by 779 · see citing works
Fundamental Aspects of Protein−Protein Association Kinetics
Schreiber, G., Haran, G., & Zhou, H. (2009) · Chemical Reviews · doi:10.1021/cr800373w · Cited by 739 · see citing works
Uversky, V. N. (2017) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2016.10.015 · Cited by 707 · see citing works
Extreme disorder in an ultrahigh-affinity protein complex
Borgia, A., Borgia, M. B., Bugge, K., Kissling, V. M., Heidarsson, P. O., Fernandes, C. B., Sottini, A., Soranno, A., Buholzer, K. J., Nettels, D., et al. (2018) · Nature · doi:10.1038/nature25762 · Cited by 653 · see citing works
Atomic structure of the MAP kinase ERK2 at 2.3 A resolution
Zhang, F., Strand, A., Robbins, D., Cobb, M. H., & Goldsmith, E. J. (1994) · Nature · doi:10.1038/367704a0 · Cited by 592 · see citing works
Kinetics of protein-protein association explained by Brownian dynamics computer simulation.
Northrup, S. H., & Erickson, H. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.8.3338 · Cited by 572 · see citing works
A decade and a half of protein intrinsic disorder: Biology still waits for physics
Uversky, V. (2013) · Protein Science · doi:10.1002/pro.2261 · Cited by 478 · see citing works
Intrinsically Disordered Proteins and Their “Mysterious” (Meta)Physics
Uversky, V. (2019) · Frontiers of Physics · doi:10.3389/fphy.2019.00010 · Cited by 449 · see citing works
Jacobs, D., Glossip, D., Xing, H., Muslin, A. J., & Kornfeld, K. (1999) · Genes & Development · doi:10.1101/gad.13.2.163 · Cited by 439 · see citing works
GROMACS - A PARALLEL COMPUTER FOR MOLECULAR-DYNAMICS SIMULATIONS
Bekker, H., Berendsen, H., Dijkstra, E., Achterop, S., Vondrumen, R., van der Spoel, D., Sijbers, A., Keegstra, H., & Renardus, M. (1993) · University of Groningen research database (University of Groningen / Centre for Information Technology) · Cited by 438 · see citing works
ILLINGWORTH, J. A. (1987) · Biochemical Education · doi:10.1016/0307-4412(87)90120-8 · Cited by 368 · see citing works
Brownian dynamics simulation of diffusion-influenced bimolecular reactions
Northrup, S. H., Allison, S. A., & McCammon, J. A. (1984) · The Journal of Chemical Physics · doi:10.1063/1.446900 · Cited by 360 · see citing works
Diffusion Measurements, at 1°, of Aqueous Solutions of Amino Acids, Peptides and Sugars
Longsworth, L. G. (1952) · Journal of the American Chemical Society · doi:10.1021/ja01136a059 · Cited by 348 · see citing works
Diffusion Measurements, at 25°, of Aqueous Solutions of Amino Acids, Peptides and Sugars
Longsworth, L. G. (1953) · Journal of the American Chemical Society · doi:10.1021/ja01118a065 · Cited by 330 · see citing works
Docking Motif Interactions in MAP Kinases Revealed by Hydrogen Exchange Mass Spectrometry
Lee, T., Hoofnagle, A. N., Kabuyama, Y., Stroud, J., Min, X., Goldsmith, E. J., Chen, L., Resing, K. A., & Ahn, N. G. (2004) · Molecular Cell · doi:10.1016/s1097-2765(04)00161-3 · Cited by 282 · see citing works
MEK1/2 dual-specificity protein kinases: Structure and regulation
Roskoski, R. J. (2011) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2011.11.145 · Cited by 277 · see citing works
Huang, Y., & Liu, Z. (2009) · Journal of Molecular Biology · doi:10.1016/j.jmb.2009.09.010 · Cited by 266 · see citing works
Möglich, A., Joder, K., & Kiefhaber, T. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0604748103 · Cited by 248 · see citing works
An ERK2 docking site in the Pointed domain distinguishes a subset of ETS transcription factors
Seidel, J. J., & Graves, B. J. (2002) · Genes & Development · doi:10.1101/gad.950902 · Cited by 182 · see citing works
Fuzziness: linking regulation to protein dynamics
Fuxreiter, M. (2011) · Molecular BioSystems · doi:10.1039/c1mb05234a · Cited by 180 · see citing works
Effect of rotation on the diffusion-controlled rate of ligand-protein association.
Hill, T. L. (1975) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.72.12.4918 · Cited by 166 · see citing works
Sheridan, D. L., Kong, Y., Parker, S. A., Dalby, K. N., & Turk, B. E. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m801074200 · Cited by 147 · see citing works
Structure of the Ets-1 pointed domain and mitogen-activated protein kinase phosphorylation site
Slupsky, C. M., Gentile, L. N., Donaldson, L. W., Mackereth, C. D., Seidel, J. J., Graves, B. J., & McIntosh, L. P. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.21.12129 · Cited by 139 · see citing works
Multiple Regions of MAP Kinase Phosphatase 3 Are Involved in Its Recognition and Activation by ERK2
Zhou, B., Wu, L., Shen, K., Zhang, J., Lawrence, D. S., & Zhang, Z. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m009753200 · Cited by 116 · see citing works
Jacobs, D., Beitel, G. J., Clark, S. G., Horvitz, H. R., & Kornfeld, K. (1998) · Genetics · doi:10.1093/genetics/149.4.1809 · Cited by 109 · see citing works
A Bipartite Mechanism for ERK2 Recognition by Its Cognate Regulators and Substrates
Zhang, J., Zhou, B., Zheng, C.-F., & Zhang, Z. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m303909200 · Cited by 92 · see citing works
Modeling protein association mechanisms and kinetics
Zhou, H., & Bates, P. A. (2013) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2013.06.014 · Cited by 90 · see citing works
A simple method for determining the mean passage time for diffusion controlled processes
Deutch, J. M. (1980) · The Journal of Chemical Physics · doi:10.1063/1.440666 · Cited by 73 · see citing works
Diversity in Structure and Function of the Ets Family PNT Domains
Mackereth, C. D., Schärpf, M., Gentile, L. N., MacIntosh, S. E., Slupsky, C. M., & McIntosh, L. P. (2004) · Journal of Molecular Biology · doi:10.1016/j.jmb.2004.07.094 · Cited by 67 · see citing works
ERK as a Model for Systems Biology of Enzyme Kinetics in Cells
Futran, A. S., Link, A. J., Seger, R., & Shvartsman, S. Y. (2013) · Current Biology · doi:10.1016/j.cub.2013.09.033 · Cited by 53 · see citing works
Proximity-Induced Catalysis by the Protein Kinase ERK2
Rainey, M. A., Callaway, K., Barnes, R., Wilson, B., & Dalby, K. N. (2005) · Journal of the American Chemical Society · doi:10.1021/ja052915p · Cited by 52 · see citing works
Examining Docking Interactions on ERK2 with Modular Peptide Substrates
Lee, S., Warthaka, M., Yan, C., Kaoud, T. S., Ren, P. Y., & Dalby, K. N. (2011) · Biochemistry · doi:10.1021/bi201103b · Cited by 48 · see citing works
Waas, W. F., & Dalby, K. N. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m110523200 · Cited by 48 · see citing works
Properties and Regulation of a Transiently Assembled ERK2·Ets-1 Signaling Complex
Callaway, K., Rainey, M. A., Riggs, A., Abramczyk, O., & Dalby, K. N. (2006) · Biochemistry · doi:10.1021/bi0610451 · Cited by 45 · see citing works
Waas, W. F., Rainey, M. A., Szafranska, A. E., & Dalby, K. N. (2003) · Biochemistry · doi:10.1021/bi0348617 · Cited by 36 · see citing works
Abramczyk, O., Rainey, M. A., Barnes, R., Martin, L., & Dalby, K. N. (2007) · Biochemistry · doi:10.1021/bi7002058 · Cited by 34 · see citing works
Callaway, K., Waas, W. F., Rainey, M. A., Ren, P., & Dalby, K. N. (2010) · Biochemistry · doi:10.1021/bi100199q · Cited by 32 · see citing works
Force field‐dependent solution properties of glycine oligomers
Drake, J. A., & Pettitt, B. M. (2015) · Journal of Computational Chemistry · doi:10.1002/jcc.23934 · Cited by 26 · see citing works
Lee, S., Warthaka, M., Yan, C., Kaoud, T. S., Piserchio, A., Ghose, R., Ren, P., & Dalby, K. N. (2011) · PLoS ONE · doi:10.1371/journal.pone.0018594 · Cited by 26 · see citing works
Piserchio, A., Warthaka, M., Kaoud, T. S., Callaway, K., Dalby, K. N., & Ghose, R. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1702973114 · Cited by 25 · see citing works
Kinetic network model to explain gain-of-function mutations in ERK2 enzyme
Misiura, M. M., & Kolomeisky, A. B. (2019) · The Journal of Chemical Physics · doi:10.1063/1.5088647 · Cited by 4 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Intrinsically disordered proteins play diverse roles in cell signaling
Bondos, S. E., Dunker, A. K., & Uversky, V. N. (2022) · Cell Communication and Signaling · doi:10.1186/s12964-022-00821-7 · Cited by 222 · see citing works
Interplay of Affinity and Surface Tethering in Protein Recognition
Imran, A., Moyer, B. S., Wolfe, A. J., Cosgrove, M. S., Makarov, D. E., & Movileanu, L. (2022) · The Journal of Physical Chemistry Letters · doi:10.1021/acs.jpclett.2c00621 · Cited by 21 · see citing works
Evaluation of Nanopore Sensor Design Using Electrical and Optical Analyses
Mayse, L. A., Imran, A., Wang, Y., Ahmad, M., Oot, R. A., Wilkens, S., & Movileanu, L. (2023) · ACS Nano · doi:10.1021/acsnano.3c02532 · Cited by 14 · see citing works
Brace, A., Salim, M., Subbiah, V., Ma, H., Emani, M. K., Trifa, A., Clyde, A., Adams, C., Uram, T. D., Yoo, H., et al. (2021) · Platform for Advanced Scientific Computing Conference (PASC) · doi:10.1145/3468267.3470578 · Cited by 10 · see citing works
Sun, B., & Kekenes-Huskey, P. M. (2023) · Quarterly Reviews of Biophysics · doi:10.1017/s003358352300001x · Cited by 9 · see citing works
Strugo, N., Burstein, C., Hossain, S. S., Nago, N., Khamis, H., & Kaplan, A. (2025) · Nature Communications · doi:10.1038/s41467-025-67217-2 · Cited by 6 · see citing works
Badyaev, A. V., Moreno, C. S., Lee, C. A., Britton, S. E., Johnstone, L. M., & Duckworth, R. A. (2026) · Proceedings of the Royal Society B Biological Sciences · doi:10.1098/rspb.2025.2393 · Cited by 4 · see citing works
Introducing intrinsic disorder reduces electrostatic steering in protein-protein interactions
Gao, M., Han, Y., Zeng, Y., Su, Z., & Huang, Y. (2021) · Biophysical Journal · doi:10.1016/j.bpj.2021.06.021 · Cited by 5 · see citing works
Wang, J., Chang, H., Quan, X., Dai, X., Wang, Y., Wang, C., Zhang, S., & Shan, C. (2023) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2023.125196 · Cited by 4 · see citing works
Kar, M. M., Bhargava, P., & Barik, A. (2023) · Lecture notes in computer science · doi:10.1007/978-3-031-34953-9_28
- Authors
- Misiura, M. M., & Kolomeisky, A. B.
- Affiliations
- Center for Theoretical Biological Physics (US)
- Corresponding author
- Kolomeisky, Anatoly B.
- Venue
- The Journal of Physical Chemistry B
- Publisher
- American Chemical Society (ACS)
- Published
- 2019-12-05
- Volume
- 124
- Issue
- 1
- Pages
- 20-27
- ISSN
- 1520-5207 (ISSN-L)
- 1520-6106
- OpenAlex
- W2993821692
- Cited by
- 10
- References
- 57
- Citations by year
- 2026: 1 · 2025: 1 · 2023: 4 · 2022: 2 · 2021: 2
- FWCI
- 0.33
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- The Journal of Physical Chemistry B (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Division of Chemistry (CHE-1664218)
- Welch Foundation (C-1559)
- Division of Physics (PHY-1427654)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Diffusion and Search Dynamics
- Physical Sciences › Mathematics › Modeling and Simulation › Fractional Differential Equations Solutions
- Keywords
- intrinsically disordered regions, protein-protein interaction, association kinetics, binding sites, RAS/MAPK pathway, Brownian dynamics, reaction rate
- MeSH terms
- Protein Domains, Binding Sites, Humans, Protein Binding, Signal Transduction, Protein Structure, Tertiary, Mitogen-Activated Protein Kinase 1, Molecular Dynamics Simulation, Intrinsically Disordered Proteins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
