How a Highly Acidic SH3 Domain Binds to Its Intrinsically Disordered Partner through the Formation of an Encounter Complex Intermediate.
8 affiliations
- 1Eastern New Mexico University, Portales, New Mexico88130, United States.
- 2University of Minnesota, Minneapolis, Minnesota55455, United States.
- 3Skidmore College, Saratoga Springs, New York12866, United States.
- 4University of Liverpool, LiverpoolL69 7ZX, U.K.
- 5University of California, Merced, California95343, United States.
- 6eBERLight, Advanced Photon Source, Argonne National Laboratory, Lemont, Illinois60439, United States.
- 7University of New England, Biddeford, Maine04005, United States.
- 8Loyola University, Chicago, Illinois60660, United States.
Abstract
Electrostatic interactions often play a role in determining the thermodynamic and kinetic properties of protein-protein interactions. However, the role of long-range electrostatic interactions in intrinsically disordered protein (IDP) binding is less clear, as they often bind in multiple steps, including initial formation of a disordered encounter complex, followed by rearrangement into the bound state. We varied the salt concentration to probe the role of long-range electrostatic interactions in the binding of the highly charged AbpSH3 domain and the oppositely charged IDP ArkA. Using isothermal titration calorimetry, we observed that salt enthalpically destabilizes the bound complex. Molecular dynamics and NMR experiments revealed that salt has little effect on the bound state structure. However, simulations show that salt destabilizes the encounter complex intermediate, which primarily affects the association rate as measured by NMR. Consistent with these results, salt has the largest stabilizing effect on the apo SH3 domain, as cations substitute for the transient and long-range electrostatic interactions that can form with ArkA in the complex. We revealed a detailed picture of how a highly charged domain uses long-range, fuzzy, electrostatic interactions to help reach the bound state, a mechanism that is likely common among other highly charged domains that bind IDPs.
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BibTeX
@article{jaramillomartinez2026highly,
title = {{How a Highly Acidic SH3 Domain Binds to Its Intrinsically Disordered Partner through the Formation of an Encounter Complex Intermediate.}},
author = {Valeria Jaramillo-Martinez and Ritika Kukreja and Michaela R Cohen and Ally Mujica and Samuel Barton and Oluebube C Onwuzulu and Jorge Cardoso and Matthew J Dominguez and Isabelle M Kekwick and Jaden Ali and Gemma M Bell and Sydney Rice and Daniela Poaquiza and Colin McClure and Frida Anguiano and Michael P Latham and K Aurelia Ball and Elliott J Stollar},
journal = {The journal of physical chemistry. B},
year = {2026},
month = oct,
doi = {10.1021/acs.jpcb.6c05098},
url = {https://europepmc.org/article/MED/42917248},
note = {CC BY},
}
RIS
TY - JOUR
TI - How a Highly Acidic SH3 Domain Binds to Its Intrinsically Disordered Partner through the Formation of an Encounter Complex Intermediate.
AU - Valeria Jaramillo-Martinez
AU - Ritika Kukreja
AU - Michaela R Cohen
AU - Ally Mujica
AU - Samuel Barton
AU - Oluebube C Onwuzulu
AU - Jorge Cardoso
AU - Matthew J Dominguez
AU - Isabelle M Kekwick
AU - Jaden Ali
AU - Gemma M Bell
AU - Sydney Rice
AU - Daniela Poaquiza
AU - Colin McClure
AU - Frida Anguiano
AU - Michael P Latham
AU - K Aurelia Ball
AU - Elliott J Stollar
PY - 2026
DA - 2026/10/01
JO - The journal of physical chemistry. B
DO - 10.1021/acs.jpcb.6c05098
UR - https://europepmc.org/article/MED/42917248
AB - Electrostatic interactions often play a role in determining the thermodynamic and kinetic properties of protein-protein interactions. However, the role of long-range electrostatic interactions in intrinsically disordered protein (IDP) binding is less clear, as they often bind in multiple steps, including initial formation of a disordered encounter complex, followed by rearrangement into the bound state. We varied the salt concentration to probe the role of long-range electrostatic interactions in the binding of the highly charged AbpSH3 domain and the oppositely charged IDP ArkA. Using isothermal titration calorimetry, we observed that salt enthalpically destabilizes the bound complex. Molecular dynamics and NMR experiments revealed that salt has little effect on the bound state structure. However, simulations show that salt destabilizes the encounter complex intermediate, which primarily affects the association rate as measured by NMR. Consistent with these results, salt has the largest stabilizing effect on the apo SH3 domain, as cations substitute for the transient and long-range electrostatic interactions that can form with ArkA in the complex. We revealed a detailed picture of how a highly charged domain uses long-range, fuzzy, electrostatic interactions to help reach the bound state, a mechanism that is likely common among other highly charged domains that bind IDPs.
SN - 1520-6106
SN - 1520-5207
ER -