Phosphotyrosine couples peptide binding and SHP2 activation via a dynamic allosteric network
| Autor: | Justyna Sikorska, Vittoria Nanna, Teresa Carlomagno, John Kirkpatrick, Michelangelo Marasco |
|---|---|
| Přispěvatelé: | HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany. |
| Rok vydání: | 2021 |
| Předmět: |
animal structures
Phosphatase Allosteric regulation Biophysics Peptide binding Protein tyrosine phosphatase Molecular dynamics SH2 domain Biochemistry 03 medical and health sciences NMR spectroscopy 0302 clinical medicine Structural Biology PD-1 Genetics Extracellular Allosteric coupling ComputingMethodologies_COMPUTERGRAPHICS 030304 developmental biology 0303 health sciences Phosphopeptide Chemistry Computer Science Applications 030220 oncology & carcinogenesis SHP2 TP248.13-248.65 Research Article Biotechnology Proto-oncogene tyrosine-protein kinase Src |
| Zdroj: | Computational and Structural Biotechnology Journal, Vol 19, Iss, Pp 2398-2415 (2021) Computational and Structural Biotechnology Journal Computational and structural biotechnology journal Netherlands |
| ISSN: | 2001-0370 |
| Popis: | Graphical abstract SHP2 is a ubiquitous protein tyrosine phosphatase, whose activity is regulated by phosphotyrosine (pY)-containing peptides generated in response to extracellular stimuli. Its crystal structure reveals a closed, auto-inhibited conformation in which the N-terminal Src homology 2 (N-SH2) domain occludes the catalytic site of the phosphatase (PTP) domain. High-affinity mono-phosphorylated peptides promote catalytic activity by binding to N-SH2 and disrupting the interaction with the PTP. The mechanism behind this process is not entirely clear, especially because N-SH2 is incapable of accommodating complete peptide binding when SHP2 is in the auto-inhibited state. Here, we show that pY performs an essential role in this process; in addition to its contribution to overall peptide-binding energy, pY-recognition leads to enhanced dynamics of the N-SH2 EF and BG loops via an allosteric communication network, which destabilizes the N-SH2–PTP interaction surface and simultaneously generates a fully accessible binding pocket for the C-terminal half of the phosphopeptide. Subsequently, full binding of the phosphopeptide is associated with the stabilization of activated SHP2. We demonstrate that this allosteric network exists only in N-SH2, which is directly involved in the regulation of SHP2 activity, while the C-terminal SH2 domain (C-SH2) functions primarily to recruit high-affinity bidentate phosphopeptides. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|