Positive feedback in Ras activation by full-length SOS arises from autoinhibition release mechanism

Ren, He; Lee, Albert A.; Lew, L.J. Nugent; DeGrandchamp, Joseph B.; Groves, Jay T.

doi:10.1016/j.bpj.2024.07.014

Biophysical Journal

2024

DOI: 10.1016/j.bpj.2024.07.014

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Positive feedback in Ras activation by full-length SOS arises from autoinhibition release mechanism

He Ren,

Albert A. Lee,

L.J. Nugent Lew

et al.

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2024

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References 40 publications

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Bridging molecular to cellular scales for models of membrane receptor signaling

Peterson,

Slepchenko,

Loew

2024

Preprint

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Biochemical interactions at membranes are the starting points for cell signaling networks. But bimolecular reaction kinetics are difficult to experimentally measure on 2-dimensional membranes and are usually measured in volumetric in vitro assays. Membrane tethering produces confinement and steric effects that will significantly impact binding rates in ways that are not readily estimated from volumetric measurements. Also, there are situations when 2D reactions do not conform to simple kinetics. Here we show how highly coarse-grained molecular simulations using the SpringSaLaD software can be used to estimate membrane-tethered rate constants from experimentally determined volumetric kinetics. The approach is validated using an analytical solution for dimerization of binding sites anchored via stiff linkers. This approach can provide 2-dimensional bimolecular rate constants to parameterize cell-scale models of receptor-mediated signaling. We explore how factors such as molecular reach, steric effects, disordered domains, local concentration and diffusion affect the kinetics of binding. We find that for reaction-limited cases, the key determinant in converting 3D to 2D rate constant is the distance of the binding sites from the membrane. On the other hand, the mass action rate law may no longer be obeyed for diffusion-limited reaction on surfaces; the simulations reveal when this situation pertains. We then apply our approach to epidermal growth factor receptor (EGFR) mediated activation of the membrane-bound small GTPase Ras. The analysis reveals how prior binding of Ras to the allosteric site of SOS, a guanine nucleotide exchange factor (GEF) that is recruited to EGFR, significantly accelerates its catalytic activity.

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Bridging molecular to cellular scales for models of membrane receptor signaling

Peterson,

Slepchenko,

Loew

2024

Preprint

View full text Add to dashboard Cite

show abstract

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Positive feedback in Ras activation by full-length SOS arises from autoinhibition release mechanism

Cited by 1 publication

References 40 publications

Bridging molecular to cellular scales for models of membrane receptor signaling

Bridging molecular to cellular scales for models of membrane receptor signaling

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