Cosolute modulation of protein oligomerization reactions in the homeostatic timescale

Borja Mateos, Ganeko Bernardo-Seisdedos, Valentin Dietrich, Nicanor Zalba, Gabriel Ortega, Francesca Peccati, Gonzalo Jiménez-Osés, Robert Konrat, Martin Tollinger, Oscar Millet (Korresp. Autor*in)

Veröffentlichungen: Beitrag in FachzeitschriftArtikelPeer Reviewed

Abstract

Protein oligomerization processes are widespread and of crucial importance to understand degenerative diseases and healthy regulatory pathways. One particular case is the homo-oligomerization of folded domains involving domain swapping, often found as a part of the protein homeostasis in the crowded cytosol, composed of a complex mixture of cosolutes. Here, we have investigated the effect of a plethora of cosolutes of very diverse nature on the kinetics of a protein dimerization by domain swapping. In the absence of cosolutes, our system exhibits slow interconversion rates, with the reaction reaching the equilibrium within the average protein homeostasis timescale (24–48 h). In the presence of crowders, though, the oligomerization reaction in the same time frame will, depending on the protein's initial oligomeric state, either reach a pure equilibrium state or get kinetically trapped into an apparent equilibrium. Specifically, when the reaction is initiated from a large excess of dimer, it becomes unsensitive to the effect of cosolutes and reaches the same equilibrium populations as in the absence of cosolute. Conversely, when the reaction starts from a large excess of monomer, the reaction during the homeostatic timescale occurs under kinetic control, and it is exquisitely sensitive to the presence and nature of the cosolute. In this scenario (the most habitual case in intracellular oligomerization processes), the effect of cosolutes on the intermediate conformation and diffusion-mediated encounters will dictate how the cellular milieu affects the domain-swapping reaction.
OriginalspracheEnglisch
Seiten (von - bis)2067-2077
Seitenumfang11
FachzeitschriftBiophysical Journal
Jahrgang120
Ausgabenummer10
DOIs
PublikationsstatusVeröffentlicht - 18 Mai 2021

ÖFOS 2012

  • 106013 Genetik
  • 106023 Molekularbiologie
  • 106041 Strukturbiologie

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