Fundamental Aspects of Protein−Protein Association Kinetics

Schreiber, Gideon; Haran, Gilad; Zhou, Huan‐Xiang

doi:10.1021/cr800373w

Cited by 670 publications

(958 citation statements)

References 202 publications

(584 reference statements)

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“…For example, differences in ionic strengths in experimental buffers may have dramatic effects on rate constants if electrostatic steering modulates the interaction. 5,52,54 We suggest that the proposal that k on governs K d for the interactions of intrinsically disordered proteins is too simplistic, and that their mechanisms as well as those of ordered proteins, must be assessed from case to case.…”

Section: Resultsmentioning

confidence: 99%

Side-Chain Interactions Form Late and Cooperatively in the Binding Reaction between Disordered Peptides and PDZ Domains

et al. 2011

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Intrinsically disordered proteins are very common and mediate numerous protein-protein and protein-DNA interactions. While it is clear that these interactions are instrumental for the life of the mammalian cell, there is a paucity of data regarding their molecular binding mechanisms. We have here used short peptides as a model system for intrinsically disordered proteins. Linear free-energy relationships based on rate and equilibrium constants for the binding of these peptides to ordered target proteins, PDZ domains, demonstrate that native side-chain interactions form mainly after the ratelimiting barrier for binding, in a cooperative fashion. This finding suggests that these disordered peptides first form a weak encounter complex with non-native interactions.The data do not support the recent notion that the affinities of intrinsically disordered proteins towards their targets are generally governed by their association rate constants.Instead, we observe the opposite for peptide-PDZ interactions, namely that changes in K d correlate with changes in k off .3

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Section: Resultsmentioning

confidence: 99%

Side-Chain Interactions Form Late and Cooperatively in the Binding Reaction between Disordered Peptides and PDZ Domains

et al. 2011

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“…II.D), and 1000 times higher than most known protein-protein association rates. (Note, however, that some protein-protein association rates are also much larger than the predictions of Smoluchowski theory (Schreiber et al, 2009)). This apparent discrepancy in reaction rates, suggests that some form of facilitated diffusion occurs.…”

Section: Diffusion-limited Reaction Ratesmentioning

confidence: 89%

Stochastic models of intracellular transport

2013

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The interior of a living cell is a crowded, heterogenuous, fluctuating environment. Hence, a major challenge in modeling intracellular transport is to analyze stochastic processes within complex environments. Broadly speaking, there are two basic mechanisms for intracellular transport: passive diffusion and motor-driven active transport. Diffusive transport can be formulated in terms of the motion of an over-damped Brownian particle. On the other hand, active transport requires chemical energy, usually in the form of ATP hydrolysis, and can be direction specific, allowing biomolecules to be transported long distances; this is particularly important in neurons due to their complex geometry. In this review we present a wide range of analytical methods and models of intracellular transport. In the case of diffusive transport, we consider narrow escape problems, diffusion to a small target, confined and single-file diffusion, homogenization theory, and fractional diffusion. In the case of active transport, we consider Brownian ratchets, random walk models, exclusion processes, random intermittent search processes, quasisteady-state reduction methods, and mean field approximations. Applications include receptor trafficking, axonal transport, membrane diffusion, nuclear transport, protein-DNA interactions, virus trafficking, and the self-organization of subcellular structures.

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“…Let us assume that the fundamental building units are considerably larger than a phytochrome dimer, that the interactions are still of the simple bindingunbinding type and that each NB is a random closepacked structure of the fundamental building blocks. If the fundamental building blocks are particles with approximate radius 86 nm, one finds for the association rate a ∼ 10 12 /(Mmin) which is in the range of observed binding constants [37,38]. This suggests that NB formation consists of two steps: an (so far) unobserved fast nucleation step leading to the formation of macroparticles with approximate radius 86 nm, and a slow step in which the large NBs form due to binding of these macroparticles (similar to an Ostwald ripening mechanism [39]).…”

Section: Discussionmentioning

confidence: 99%

Insight into nuclear body formation of phytochromes through stochastic modelling and experiment

et al. 2018

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Spatial relocalization of proteins is crucial for the correct functioning of living cells. An interesting example of spatial ordering is the light-induced clustering of plant photoreceptor proteins. Upon irradiation by white or red light, the red light-active phytochrome, phytochrome B, enters the nucleus and accumulates in large nuclear bodies (NBs). The underlying physical process of nuclear body formation remains unclear, but phytochrome B is thought to coagulate via a simple protein-protein binding process. We measure, for the first time, the distribution of the number of phytochrome B-containing NBs as well as their volume distribution. We show that the experimental data cannot be explained by a stochastic model of nuclear body formation via simple protein-protein binding processes using physically meaningful parameter values. Rather modelling suggests that the data is consistent with a two step process: a fast nucleation step leading to macroparticles followed by a subsequent slow step in which the macroparticles bind to form the nuclear body. An alternative explanation for the observed nuclear body distribution is that the phytochromes bind to a so far unknown molecular structure. We believe it is likely this result holds more generally for other nuclear body-forming plant photoreceptors and proteins. PAPEROriginal content from this work may be used under the terms of the Creative Commons Attribution 3.0 licence.

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Fundamental Aspects of Protein−Protein Association Kinetics

Cited by 670 publications

References 202 publications

Side-Chain Interactions Form Late and Cooperatively in the Binding Reaction between Disordered Peptides and PDZ Domains

Side-Chain Interactions Form Late and Cooperatively in the Binding Reaction between Disordered Peptides and PDZ Domains

Stochastic models of intracellular transport

Insight into nuclear body formation of phytochromes through stochastic modelling and experiment

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