An allosteric interaction controls the activation mechanism of SHP2 tyrosine phosphatase.
Computer Simulation
Humans
Models, Molecular
Molecular Dynamics Simulation
Mutation
/ genetics
Protein Binding
/ genetics
Protein Conformation
Protein Domains
/ genetics
Protein Tyrosine Phosphatase, Non-Receptor Type 11
/ metabolism
Protein Tyrosine Phosphatases
/ metabolism
Signal Transduction
/ genetics
Tyrosine
/ metabolism
src Homology Domains
/ genetics
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
28 10 2020
28 10 2020
Historique:
received:
26
06
2020
accepted:
13
10
2020
entrez:
29
10
2020
pubmed:
30
10
2020
medline:
12
1
2021
Statut:
epublish
Résumé
SHP2 is a protein tyrosine phosphatase (PTP) involved in multiple signaling pathways. Mutations of SHP2 can result in Noonan syndrome or pediatric malignancies. Inhibition of wild-type SHP2 represents a novel strategy against several cancers. SHP2 is activated by binding of a phosphopeptide to the N-SH2 domain of SHP2, thereby favoring dissociation of the N-SH2 domain and exposing the active site on the PTP domain. The conformational transitions controlling ligand affinity and PTP dissociation remain poorly understood. Using molecular simulations, we revealed an allosteric interaction restraining the N-SH2 domain into a SHP2-activating and a stabilizing state. Only ligands selecting for the activating N-SH2 conformation, depending on ligand sequence and binding mode, are effective activators. We validate the model of SHP2 activation by rationalizing modified basal activity and responsiveness to ligand stimulation of several N-SH2 variants. This study provides mechanistic insight into SHP2 activation and may open routes for SHP2 regulation.
Identifiants
pubmed: 33116231
doi: 10.1038/s41598-020-75409-7
pii: 10.1038/s41598-020-75409-7
pmc: PMC7595171
doi:
Substances chimiques
Tyrosine
42HK56048U
Protein Tyrosine Phosphatase, Non-Receptor Type 11
EC 3.1.3.48
Protein Tyrosine Phosphatases
EC 3.1.3.48
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
18530Subventions
Organisme : Marie Curie
ID : 705829
Pays : United Kingdom
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