Discriminating between competing models for the allosteric regulation of oncogenic phosphatase SHP2 by characterizing its active state
| Autor: | Valerio Santucci, Paolo Calligari, Gianfranco Bocchinfuso, Lorenzo Stella |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
SHP2
Src homology 2 domain-containing phosphatase 2 CTLA-4 cytotoxic T lymphocyte-associated antigen 4 NSML Noonan syndrome with multiple lentigines Allosteric regulation Phosphatase Biophysics Protein Data Bank (RCSB PDB) Protein tyrosine phosphatase FRET Förster resonance energy transfer SH2 domain Biochemistry PD-1 programmed cell death protein 1 RMSF root mean square fluctuation RMSD root mean square deviation SAXS small angle X-ray scattering PMF potential of mean force Settore CHIM/02 Structural Biology NS Noonan syndrome Genetics Protein flexibility pY phosphorylated tyrosine Binding site PDB protein data bank ComputingMethodologies_COMPUTERGRAPHICS JMML juvenile myelomonocytic leukemia biology Chemistry Wild type Active site SHP2 regulatory mechanism REMD replica exchange molecular dynamics MD molecular dynamics SIRPalpha signal regulatory protein alpha Computer Science Applications Inter-domain dynamics Replica exchange molecular dynamics simulations biology.protein SASA solvent accessible surface area RTK receptor tyrosine kinase BTLA B and T lymphocyte attenuator PTP protein tyrosine phosphatase TP248.13-248.65 SH2 Src homology 2 Biotechnology Research Article |
| Zdroj: | Computational and Structural Biotechnology Journal Computational and Structural Biotechnology Journal, Vol 19, Iss, Pp 6125-6139 (2021) |
| ISSN: | 2001-0370 |
| Popis: | Graphical abstract The Src-homology 2 domain containing phosphatase 2 (SHP2) plays a critical role in crucial signaling pathways and is involved in oncogenesis and in developmental disorders. Its structure includes two SH2 domains (N-SH2 and C-SH2), and a protein tyrosine phosphatase (PTP) domain. Under basal conditions, SHP2 is auto-inhibited, with the N-SH2 domain blocking the PTP active site. Activation involves a rearrangement of the domains that makes the catalytic site accessible, coupled to the association between the SH2 domains and cognate proteins containing phosphotyrosines. Several aspects of this transition are debated and competing mechanistic models have been proposed. A crystallographic structure of SHP2 in an active state has been reported (PDB code 6crf), but several lines of evidence suggests that it is not fully representative of the conformations populated in solution. To clarify the structural rearrangements involved in SHP2 activation, enhanced sampling simulations of the autoinhibited and active states have been performed, for wild type SHP2 and its pathogenic E76K variant. Our results demonstrate that the crystallographic conformation of the active state is unstable in solution, and multiple interdomain arrangements are populated, thus allowing association to bisphosphorylated sequences. Contrary to a recent proposal, activation is coupled to the conformational changes of the N-SH2 binding site, which is significantly more accessible in the active sate, rather than to the structure of the central β-sheet of the domain. In this coupling, a previously undescribed role for the N-SH2 BG loop emerged. |
| Databáze: | OpenAIRE |
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