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Phosphorylation releases constraints to domain motion in ERK2.

Protein motions control enzyme catalysis through mechanisms that are incompletely understood. Here NMR [sup.13]C relaxation dispersion experiments were used to monitor changes in side-chain motions that occur in response to activation by phosphorylation of the MAP kinase ERK2. NMR data for the methy... Full description

Journal Title: Proceedings of the National Academy of Sciences of the United States of America February 18, 2014, Vol.111(7), pp.2506-2511
Main Author: Xiao, Yao
Other Authors: Lee, Thomas , Latham, Michael Parker , Warner, Lisa Rose , Tanimoto, Akiko , Pardi, Arthur , Ahn, Natalie G
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1091-6490 ; DOI: 1091-6490 ; DOI: 10.1073/pnas.1318899111
Link: http://search.proquest.com/docview/1500683408/?pq-origsite=primo
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title: Phosphorylation releases constraints to domain motion in ERK2.
format: Article
creator:
  • Xiao, Yao
  • Lee, Thomas
  • Latham, Michael Parker
  • Warner, Lisa Rose
  • Tanimoto, Akiko
  • Pardi, Arthur
  • Ahn, Natalie G
subjects:
  • Animals–Physiology
  • Enzyme Activation–Chemistry
  • Escherichia Coli–Metabolism
  • Magnetic Resonance Spectroscopy–Metabolism
  • Mitogen-Activated Protein Kinase 1–Metabolism
  • Models, Molecular–Metabolism
  • Phosphorylation–Metabolism
  • Protein Structure, Tertiary–Metabolism
  • Rats–Metabolism
  • Mapk1 Protein, Rat
  • Mitogen-Activated Protein Kinase 1
ispartof: Proceedings of the National Academy of Sciences of the United States of America, February 18, 2014, Vol.111(7), pp.2506-2511
description: Protein motions control enzyme catalysis through mechanisms that are incompletely understood. Here NMR [sup.13]C relaxation dispersion experiments were used to monitor changes in side-chain motions that occur in response to activation by phosphorylation of the MAP kinase ERK2. NMR data for the methyl side chains on Ile, Leu, and Val residues showed changes in conformational exchange dynamics in the microsecond-to-millisecond time regime between the different activity states of ERK2. In inactive, unphosphorylated ERK2, localized conformational exchange was observed among methyl side chains, with little evidence for coupling between residues. Upon dual phosphorylation by MAP kinase kinase 1, the dynamics of assigned methyls in ERK2 were altered throughout the conserved kinase core, including many residues in the catalytic pocket. The majority of residues in active ERK2 fit to a single conformational exchange process, with [k.sub.ex] [approximately equal to] 300 [S.sup.-1] ([k.sub.AB] [approximately equal to] 240 [s.sup.-1]/[k.sub.BA] [approximately equal to] 60 [s.sup.-1]) and [P.sub.A]/[P.sub.B] [approximately equal to] 20%/80%, suggesting global domain motions involving interconversion between two states. A mutant of ERK2, engineered to enhance conformational mobility at the hinge region linking the N- and C-terminal domains, also induced two-state conformational exchange throughout the kinase core, with exchange properties of [k.sub.ex] [approximately equal to] 500 [s.sup.-1] ([k.sub.AB] [approximately equal to] 15 [s.sup.-1]/[k.sub.BA] [approximately equal to] 485 [s.sup.-1]) and [P.sub.A]/[P.sub.B] [approximately equal to] 97%/3%. Thus, phosphorylation and activation of ERK2 lead to a dramatic shift in conformational exchange dynamics, likely through release of constraints at the hinge. www.pnas.org/cgi/doi/10.1073/pnas.1318899111
language: eng
source:
identifier: E-ISSN: 1091-6490 ; DOI: 1091-6490 ; DOI: 10.1073/pnas.1318899111
fulltext: fulltext
issn:
  • 10916490
  • 1091-6490
url: Link


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titlePhosphorylation releases constraints to domain motion in ERK2.
creatorXiao, Yao ; Lee, Thomas ; Latham, Michael Parker ; Warner, Lisa Rose ; Tanimoto, Akiko ; Pardi, Arthur ; Ahn, Natalie G
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descriptionProtein motions control enzyme catalysis through mechanisms that are incompletely understood. Here NMR [sup.13]C relaxation dispersion experiments were used to monitor changes in side-chain motions that occur in response to activation by phosphorylation of the MAP kinase ERK2. NMR data for the methyl side chains on Ile, Leu, and Val residues showed changes in conformational exchange dynamics in the microsecond-to-millisecond time regime between the different activity states of ERK2. In inactive, unphosphorylated ERK2, localized conformational exchange was observed among methyl side chains, with little evidence for coupling between residues. Upon dual phosphorylation by MAP kinase kinase 1, the dynamics of assigned methyls in ERK2 were altered throughout the conserved kinase core, including many residues in the catalytic pocket. The majority of residues in active ERK2 fit to a single conformational exchange process, with [k.sub.ex] [approximately equal to] 300 [S.sup.-1] ([k.sub.AB] [approximately equal to] 240 [s.sup.-1]/[k.sub.BA] [approximately equal to] 60 [s.sup.-1]) and [P.sub.A]/[P.sub.B] [approximately equal to] 20%/80%, suggesting global domain motions involving interconversion between two states. A mutant of ERK2, engineered to enhance conformational mobility at the hinge region linking the N- and C-terminal domains, also induced two-state conformational exchange throughout the kinase core, with exchange properties of [k.sub.ex] [approximately equal to] 500 [s.sup.-1] ([k.sub.AB] [approximately equal to] 15 [s.sup.-1]/[k.sub.BA] [approximately equal to] 485 [s.sup.-1]) and [P.sub.A]/[P.sub.B] [approximately equal to] 97%/3%. Thus, phosphorylation and activation of ERK2 lead to a dramatic shift in conformational exchange dynamics, likely through release of constraints at the hinge. www.pnas.org/cgi/doi/10.1073/pnas.1318899111
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