Εξειδίκευση τύπου :	Άρθρο σε επιστημονικό περιοδικό
Τίτλος:	Mechanism of SHP2 activation by bis-Tyr-phosphorylated Gab1
Δημιουργός/Συγγραφέας:	Machner, Lisa Shaikhqasem, Alaa Gruber, Tobias Hamdi, Farzad Breithaupt, Constanze Kniest, Judith Wiebe, Felix Lewitzky, Marc Parthier, Christoph Kyrilis, Fotis L Balbach, Jochen [EL] Καστρίτης, Παναγιώτης[EN] Kastritis, Panagiotis Feller, Stephan M Stubbs, Milton T
Ημερομηνία:	2025-12-22
Γλώσσα:	Αγγλικά
ISSN:	09692126
DOI:	10.1016/j.str.2025.11.018
Άλλο:	41435833
Περίληψη:	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 pY627pY659-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.
Τίτλος πηγής δημοσίευσης:	Structure (London, England : 1993)
Θεματική Κατηγορία:	[EL] Βιοχημεία[EN] Biochemistry [EL] Δομική Βιολογία[EN] Structural Biology [EL] Μοριακή Βιολογία[EN] Molecular Biology
Λέξεις-Κλειδιά:	NMR SH2 domain X-ray crystallography allosteric activation electron crystallography isothermal calorimetry protein dynamics protein structure signal transduction tyrosine phosphatase
Κάτοχος πνευματικών δικαιωμάτων:	© 2025 The Authors. Published by Elsevier Inc.
Όροι και προϋποθέσεις δικαιωμάτων:	This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Ηλεκτρονική διεύθυνση στον εκδότη (link):	https://doi.org/10.1016/j.str.2025.11.018
Εμφανίζεται στις συλλογές:	Ινστιτούτο Χημικής Βιολογίας - Επιστημονικό έργο