SHP-1 tyrosine phosphatase binding to c-Src kinase phosphor-dependent conformations: A comparative structural framework.
PLoS One
; 18(1): e0278448, 2023.
Article
em En
| MEDLINE
| ID: mdl-36638102
ABSTRACT
SHP-1 is a cytosolic tyrosine phosphatase that is primarily expressed in hematopoietic cells. It acts as a negative regulator of numerous signaling pathways and controls multiple cellular functions involved in cancer pathogenesis. This study describes the binding preferences of SHP-1 (pY536) to c-Srcopen (pY416) and c-Srcclose (pY527) through in silico approaches. Molecular dynamics simulation analysis revealed more conformational changes in c-Srcclose upon binding to SHP-1, as compared to its active/open conformation that is stabilized by the cooperative binding of the C-SH2 domain and C-terminal tail of SHP-1 to c-Src SH2 and KD. In contrast, c-Srcclose and SHP-1 interaction is mediated by PTP domain-specific WPD-loop (WPDXGXP) and Q-loop (QTXXQYXF) binding to c-Srcclose C-terminal tail residues. The dynamic correlation analysis demonstrated a positive correlation for SHP-1 PTP with KD, SH3, and the C-terminal tail of c-Srcclose. In the case of the c-Srcopen-SHP-1 complex, SH3 and SH2 domains of c-Srcopen were correlated to C-SH2 and the C-terminal tail of SHP-1. Our findings reveal that SHP1-dependent c-Src activation through dephosphorylation relies on the conformational shift in the inhibitory C-terminal tail that may ease the recruitment of the N-SH2 domain to phosphotyrosine residue, resulting in the relieving of the PTP domain. Collectively, this study delineates the intermolecular interaction paradigm and underlying conformational readjustments in SHP-1 due to binding with the c-Src active and inactive state. This study will largely help in devising novel therapeutic strategies for targeting cancer development.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Domínios de Homologia de src
/
Proteína Tirosina Fosfatase não Receptora Tipo 6
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Proteína Tirosina Quinase CSK
Idioma:
En
Revista:
PLoS One
Assunto da revista:
CIENCIA
/
MEDICINA
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Paquistão