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TitleMechanism of SHP2 activation by bis-Tyr-phosphorylated Gab1.
Journal, issue, pagesStructure, Year 2025
Publish dateFeb 27, 2025 (structure data deposition date)
AuthorsLisa Machner / Alaa Shaikhqasem / Tobias Gruber / Farzad Hamdi / Constanze Breithaupt / Judith Kniest / Felix Wiebe / Marc Lewitzky / Christoph Parthier / Fotis L Kyrilis / Jochen Balbach / Panagiotis L Kastritis / Stephan M Feller / Milton T Stubbs /
PubMed AbstractThe non-receptor tyrosine phosphatase SHP2 (SH2 domain-containing protein tyrosine phosphatase 2) (PTPN11) is a regulator of diverse cellular functions including mitogenic activation and cell ...The non-receptor tyrosine phosphatase SHP2 (SH2 domain-containing protein tyrosine phosphatase 2) (PTPN11) is a regulator of diverse cellular functions including mitogenic activation and cell migration. It comprises two tandem Src-homology 2 (SH2) domains followed by the catalytic domain and is autoinhibited by the N-terminal SH2 domain blocking access to the active site. Mutations influencing auto-inhibition have been implicated in cancer and other diseases, and allosteric inhibitors have been developed that stabilize the inactive state. Here, we show that the intrinsically disordered bis-phosphorylated SHP2-activating peptide pYpY-Gab1 binds to both SH2 domains, undergoing partial ordering in the process. In addition to eliciting changes in SH2 domain dynamics, the peptide reorganizes their relative orientations to generate a new SH2-SH2 interface. Our data suggest an active conformation for SHP2 that is also applicable to the hematopoietic cell-specific SHP1 (PTPN6), shedding light on the activation mechanism of both enzymes and paving the way for the development of novel compounds to modulate SHP2 activity.
External linksStructure / PubMed:41435833
MethodsX-ray diffraction / EM (electron crystallography)
Resolution2.08 - 3.2 Å
Structure data

PDB-9qa5:
Structure of the N-SH2 domain of SHP2 in complex with the phosphoY627-Gab1 (613-651) peptide
Method: X-RAY DIFFRACTION / Resolution: 2.08 Å

PDB-9qcd:
Micro-ED structure of the NSH2-CSH2 tandem domain of SHP2 in complex with the bis-phosphorylated pY627-pY659-Gab1 (613-694) peptide
Method: ELECTRON CRYSTALLOGRAPHY / Resolution: 3.2 Å

Chemicals

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
KeywordsSIGNALING PROTEIN / SH2-domain / phosphatase / PTPN11 / phospho-tyrosine

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