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

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Author(s)

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

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Publication details

JournalCurrent Biology
DateAccepted/In press - 16 Dec 2019
DateE-pub ahead of print (current) - 13 Feb 2020
Volume30
Number of pages13
Pages (from-to)877-882
Early online date13/02/20
Original languageEnglish

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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© 2019 Elsevier Ltd. This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy.

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