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Review
. 2019 Dec:53:118-124.
doi: 10.1016/j.cbpa.2019.08.007. Epub 2019 Oct 2.

How do DNA-bound proteins leave their binding sites? The role of facilitated dissociation

Aykut Erbaş  1 , John F Marko  2
Affiliations
Review

How do DNA-bound proteins leave their binding sites? The role of facilitated dissociation

Aykut Erbaş et al. Curr Opin Chem Biol. 2019 Dec.

Abstract

Dissociation of a protein from DNA is often assumed to be described by an off rate that is independent of other molecules in solution. Recent experiments and computational analyses have challenged this view by showing that unbinding rates (residence times) of DNA-bound proteins can depend on concentrations of nearby molecules that are competing for binding. This 'facilitated dissociation' (FD) process can occur at the single-binding site level via formation of a ternary complex, and can dominate over 'spontaneous dissociation' at low (submicromolar) concentrations. In the crowded intracellular environment FD introduces new regulatory possibilities at the level of individual biomolecule interactions.

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Figures

Figure 1:
Figure 1:. Kinetic pathways for facilitated dissociation (FD) and experimental data.
A) Competing protein from solution (gray) binds to partially exposed DNA site arising from thermal fluctuation of previously bound protein (green). In the ternary complex, each protein is weakly bound, which leads to dissociation of one or both proteins. B) Within the ternary complex, proteins can compete may interfere with one another’s binding via allostery through the substrate as well as via sterically blocking one anothers’ interactions with the DNA. C) Experimental data showing protein off-rate increasing with bulk protein concentration for a few DNA-binding proteins (see text for details). In each case the off-rate increases with solution concentration of that protein, the hallmark of facilitated dissociation.
Figure 2:
Figure 2:
A) Partially bound protein on DNA binding site. The time window during which the binding site is exposed to invading proteins from solution sets the limiting FD off rate approached at high competitor concentration. B) Schematic behavior of protein concentration-dependence of off rate: off rate increases linearly at low concentration with slope of kexch, while at higher concentrations the off rate saturates at the limiting off rate.
Figure 3:
Figure 3:
Effects of salt ions on unbinding. A) Salt weakly affects off rates via FD since there is no net ion adsorption or release. B) For spontaneous dissociation, many ions may bind the dissociating protein and DNA, resulting in a strong effect of salt concentration. C) Schematics of salt concentration versus the off rate data for the two cases [3•, 21].
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