Inference of Multisite Phosphorylation Rate Constants and their Modulation via Pathogenic Mutations

Eyan Yeung; Sarah McFann; Lewis Marsh; Emilie Sonia Dufresne; Sarah Filippi; Heather A Harrington; Stanislav Y. Shvartsman; Martin Wühr

doi:10.1016/j.cub.2019.12.052

Inference of Multisite Phosphorylation Rate Constants and their Modulation via Pathogenic Mutations

Eyan Yeung, Sarah McFann, Lewis Marsh, Emilie Sonia Dufresne, Sarah Filippi, Heather A Harrington, Stanislav Y. Shvartsman, Martin Wühr

Mathematics

Research output: Contribution to journal › Article › peer-review

Abstract

Multisite protein phosphorylation plays a critical role in cell regulation [1–3]. It is widely appreciated that the functional capabilities of multisite phosphorylation depend on the order and kinetics of phosphorylation steps, but kinetic aspects of multisite phosphorylation remain poorly understood [4–6]. Here we focus on what appears to be the simplest scenario, when a protein is phosphorylated on only two sites in a strict, well- defined order. This scenario describes the activation of ERK, a highly conserved cell signaling enzyme. We use Bayesian parameter inference in a structurally identifiable kinetic model to dissect dual phosphorylation of ERK by MEK, a kinase which is mutated in a large number of human diseases [4–6]. Our results reveal how enzyme processivity and efficiencies of individual phosphorylation steps are altered by pathogenic mutations. The presented approach, which connects specific mutations to kinetic parameters of multisite phosphorylation mechanisms, provides a systematic framework for closing the gap between studies with purified signaling enzymes and their effects in the living organism.

Original language	English
Pages (from-to)	877-882
Number of pages	13
Journal	Current Biology
Volume	30
Early online date	13 Feb 2020
DOIs	https://doi.org/10.1016/j.cub.2019.12.052
Publication status	E-pub ahead of print - 13 Feb 2020

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10.1016/j.cub.2019.12.052

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Cite this

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title = "Inference of Multisite Phosphorylation Rate Constants and their Modulation via Pathogenic Mutations",

abstract = "Multisite protein phosphorylation plays a critical role in cell regulation [1–3]. It is widely appreciated that the functional capabilities of multisite phosphorylation depend on the order and kinetics of phosphorylation steps, but kinetic aspects of multisite phosphorylation remain poorly understood [4–6]. Here we focus on what appears to be the simplest scenario, when a protein is phosphorylated on only two sites in a strict, well- defined order. This scenario describes the activation of ERK, a highly conserved cell signaling enzyme. We use Bayesian parameter inference in a structurally identifiable kinetic model to dissect dual phosphorylation of ERK by MEK, a kinase which is mutated in a large number of human diseases [4–6]. Our results reveal how enzyme processivity and efficiencies of individual phosphorylation steps are altered by pathogenic mutations. The presented approach, which connects specific mutations to kinetic parameters of multisite phosphorylation mechanisms, provides a systematic framework for closing the gap between studies with purified signaling enzymes and their effects in the living organism.",

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AU - Yeung, Eyan

AU - McFann, Sarah

AU - Marsh, Lewis

AU - Dufresne, Emilie Sonia

AU - Filippi, Sarah

AU - Harrington, Heather A

AU - Shvartsman, Stanislav Y.

AU - Wühr, Martin

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AB - Multisite protein phosphorylation plays a critical role in cell regulation [1–3]. It is widely appreciated that the functional capabilities of multisite phosphorylation depend on the order and kinetics of phosphorylation steps, but kinetic aspects of multisite phosphorylation remain poorly understood [4–6]. Here we focus on what appears to be the simplest scenario, when a protein is phosphorylated on only two sites in a strict, well- defined order. This scenario describes the activation of ERK, a highly conserved cell signaling enzyme. We use Bayesian parameter inference in a structurally identifiable kinetic model to dissect dual phosphorylation of ERK by MEK, a kinase which is mutated in a large number of human diseases [4–6]. Our results reveal how enzyme processivity and efficiencies of individual phosphorylation steps are altered by pathogenic mutations. The presented approach, which connects specific mutations to kinetic parameters of multisite phosphorylation mechanisms, provides a systematic framework for closing the gap between studies with purified signaling enzymes and their effects in the living organism.

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