Proline Hydroxylation Primes Protein Kinases for Autophosphorylation and Activation.
Amino Acid Sequence
Animals
Binding Sites
Brain Neoplasms
/ genetics
Cell Line, Tumor
Crystallography, X-Ray
Gene Expression Regulation, Neoplastic
Glioma
/ genetics
HEK293 Cells
Heterografts
Humans
Hydroxylation
Hypoxia-Inducible Factor-Proline Dioxygenases
/ genetics
Isoenzymes
/ chemistry
Mice
Mice, Nude
Mitogen-Activated Protein Kinase 14
/ chemistry
Models, Molecular
Mutation
Neuroglia
/ metabolism
Phosphorylation
Proline
/ metabolism
Protein Binding
Protein Interaction Domains and Motifs
Protein Processing, Post-Translational
Protein Serine-Threonine Kinases
/ chemistry
Protein Structure, Secondary
Protein-Tyrosine Kinases
/ chemistry
Von Hippel-Lindau Tumor Suppressor Protein
/ genetics
Dyrk Kinases
Journal
Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571
Informations de publication
Date de publication:
06 08 2020
06 08 2020
Historique:
received:
08
10
2019
revised:
25
03
2020
accepted:
11
06
2020
pubmed:
9
7
2020
medline:
26
8
2020
entrez:
9
7
2020
Statut:
ppublish
Résumé
Activation of dual-specificity tyrosine-phosphorylation-regulated kinases 1A and 1B (DYRK1A and DYRK1B) requires prolyl hydroxylation by PHD1 prolyl hydroxylase. Prolyl hydroxylation of DYRK1 initiates a cascade of events leading to the release of molecular constraints on von Hippel-Lindau (VHL) ubiquitin ligase tumor suppressor function. However, the proline residue of DYRK1 targeted by hydroxylation and the role of prolyl hydroxylation in tyrosine autophosphorylation of DYRK1 are unknown. We found that a highly conserved proline in the CMGC insert of the DYRK1 kinase domain is hydroxylated by PHD1, and this event precedes tyrosine autophosphorylation. Mutation of the hydroxylation acceptor proline precludes tyrosine autophosphorylation and folding of DYRK1, resulting in a kinase unable to preserve VHL function and lacking glioma suppression activity. The consensus proline sequence is shared by most CMGC kinases, and prolyl hydroxylation is essential for catalytic activation. Thus, formation of prolyl-hydroxylated intermediates is a novel mechanism of kinase maturation and likely a general mechanism of regulation of CMGC kinases in eukaryotes.
Identifiants
pubmed: 32640193
pii: S1097-2765(20)30423-8
doi: 10.1016/j.molcel.2020.06.021
pmc: PMC7849370
mid: NIHMS1609489
pii:
doi:
Substances chimiques
Isoenzymes
0
Proline
9DLQ4CIU6V
EGLN2 protein, human
EC 1.14.11.29
Hypoxia-Inducible Factor-Proline Dioxygenases
EC 1.14.11.29
Von Hippel-Lindau Tumor Suppressor Protein
EC 2.3.2.27
Protein-Tyrosine Kinases
EC 2.7.10.1
Protein Serine-Threonine Kinases
EC 2.7.11.1
Mitogen-Activated Protein Kinase 14
EC 2.7.11.24
VHL protein, human
EC 6.3.2.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
376-389.e8Subventions
Organisme : NCI NIH HHS
ID : R01 CA190891
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA101644
Pays : United States
Organisme : NCI NIH HHS
ID : U54 CA193313
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS061776
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA179044
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA131126
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA178546
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA239721
Pays : United States
Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests The authors declare no competing interests.
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