Scaffolding mechanism of arrestin-2 in the cRaf/MEK1/ERK signaling cascade
| Autor: | Kiae Kim, Rui-Rui Li, Vsevolod V. Gurevich, Ka Young Chung, Fan Yang, Donghee Ham, Ji Young Park, Changxiu Qu, Min Woo Yun, Jin-Peng Sun, Tina M. Iverson, Qing-Tao He |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
MAPK/ERK pathway
genetic structures Arrestins MAP Kinase Signaling System media_common.quotation_subject MAP Kinase Kinase 1 Protein Serine-Threonine Kinases environment and public health Mass Spectrometry Homologous desensitization Chlorocebus aethiops Arrestin Fluorescence Resonance Energy Transfer Animals Humans Phosphorylation Internalization Extracellular Signal-Regulated MAP Kinases Nuclear Magnetic Resonance Biomolecular beta-Arrestins media_common Mitogen-Activated Protein Kinase Kinases Multidisciplinary MAP kinase kinase kinase Kinase Chemistry Proteins Biological Sciences MAP Kinase Kinase Kinases beta-Arrestin 2 eye diseases Cell biology Rats beta-Arrestin 1 COS Cells sense organs Signal transduction biological phenomena cell phenomena and immunity Mitogen-Activated Protein Kinases Protein Processing Post-Translational Protein Binding Signal Transduction |
| Zdroj: | Proc Natl Acad Sci U S A |
| Popis: | Arrestins were initially identified for their role in homologous desensitization and internalization of G protein-coupled receptors. Receptor-bound arrestins also initiate signaling by interacting with other signaling proteins. Arrestins scaffold MAPK signaling cascades, MAPK kinase kinase (MAP3K), MAPK kinase (MAP2K), and MAPK. In particular, arrestins facilitate ERK1/2 activation by scaffolding ERK1/2 (MAPK), MEK1 (MAP2K), and Raf (MAPK3). However, the structural mechanism underlying this scaffolding remains unknown. Here, we investigated the mechanism of arrestin-2 scaffolding of cRaf, MEK1, and ERK2 using hydrogen/deuterium exchange-mass spectrometry, tryptophan-induced bimane fluorescence quenching, and NMR. We found that basal and active arrestin-2 interacted with cRaf, while only active arrestin-2 interacted with MEK1 and ERK2. The ATP binding status of MEK1 or ERK2 affected arrestin-2 binding; ATP-bound MEK1 interacted with arrestin-2, whereas only empty ERK2 bound arrestin-2. Analysis of the binding interfaces suggested that the relative positions of cRaf, MEK1, and ERK2 on arrestin-2 likely facilitate sequential phosphorylation in the signal transduction cascade. |
| Databáze: | OpenAIRE |
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