Inference of Multisite Phosphorylation Rate Constants and Their Modulation by Pathogenic Mutations

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

Research output: Contribution to journalArticle

2 Scopus citations

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 that is mutated in a large number of human diseases [7–12]. 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 enzymes and their effects in the living organism. Yeung et al. apply Bayesian parameter inference to a structurally identifiable kinetic model to dissect the dual phosphorylation of ERK by MEK, a kinase that is mutated in a large number of human diseases. They find that enzyme processivity and the catalytic efficiencies of individual phosphorylation steps can be altered by pathogenic mutations.

Original languageEnglish (US)
Pages (from-to)877-882.e6
JournalCurrent Biology
Volume30
Issue number5
DOIs
StatePublished - Mar 9 2020

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Keywords

  • Bayesian parameter inference
  • ERK
  • MAPK pathway
  • MEK
  • kinase
  • kinetic parameters
  • multisite protein phosphorylation
  • pathogenic mutations
  • phosphorylation
  • structurally identifiable kinetic model

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