The loops of the N-SH2 binding cleft do not serve as allosteric switch in SHP2 activation.
allosteric regulation
molecular dynamics simulations
phosphatases
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
27 04 2021
27 04 2021
Historique:
entrez:
23
4
2021
pubmed:
24
4
2021
medline:
1
12
2021
Statut:
ppublish
Résumé
The Src-homology-2 domain-containing phosphatase SHP2 is a critical regulator of signal transduction, being implicated in cell growth and differentiation. Activating mutations cause developmental disorders and act as oncogenic drivers in hematologic cancers. SHP2 is activated by phosphopeptide binding to the N-SH2 domain, triggering the release of N-SH2 from the catalytic PTP domain. Based on early crystallographic data, it has been widely accepted that opening of the binding cleft of N-SH2 serves as the key "allosteric switch" driving SHP2 activation. To test the putative coupling between binding cleft opening and SHP2 activation as assumed by the allosteric switch model, we critically reviewed structural data of SHP2, and we used extensive molecular dynamics (MD) simulation and free energy calculations of isolated N-SH2 in solution, SHP2 in solution, and SHP2 in a crystal environment. Our results demonstrate that the binding cleft in N-SH2 is constitutively flexible and open in solution and that a closed cleft found in certain structures is a consequence of crystal contacts. The degree of opening of the binding cleft has only a negligible effect on the free energy of SHP2 activation. Instead, SHP2 activation is greatly favored by the opening of the central β-sheet of N-SH2. We conclude that opening of the N-SH2 binding cleft is not the key allosteric switch triggering SHP2 activation.
Identifiants
pubmed: 33888588
pii: 2025107118
doi: 10.1073/pnas.2025107118
pmc: PMC8092557
pii:
doi:
Substances chimiques
Protein Tyrosine Phosphatase, Non-Receptor Type 11
EC 3.1.3.48
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Video-Audio Media
Langues
eng
Sous-ensembles de citation
IM
Déclaration de conflit d'intérêts
The authors declare no competing interest.
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