Speaker
Description
The phosphatase protein SHP2 plays a crucial role in regulating key cellular signaling pathways. Activating mutations in SHP2 have been linked to developmental disorders such as Noonan syndrome and are associated with multiple cancer types [1,2]. SHP2 has a multi-domain structure comprising two SH2 domains (N-SH2 and C-SH2) followed by a catalytic PTP domain. SH2 domains recognize and bind polypeptide sequences containing phosphotyrosine residues.
In the absence of external stimuli, SHP2 remains in a closed, autoinhibited state, where the N-SH2 domain blocks the catalytic site of the PTP domain. Activation occurs when SH2 domains interact with phosphorylated partners, leading to structural rearrangements. However, the exact role and interplay of SH2 domains in partner recruitment and binding remain only partially understood. Upon activation, N-SH2 undergoes an allosteric change which corresponds to greater accessibility of its binding site to phosphorylated sequences. We recently proposed that phosphopeptide binding to N-SH2 triggers SHP2 activation via a conformational selection mechanism [3].
Although structural data exist for both inactive and active states, the overall activation mechanism of SHP2 remains elusive. Traditional simulations face challenges due to slow interconversion rates (on the order of seconds). To address this, we employed enhanced sampling techniques, including replica exchange molecular dynamics (REMD) and metadynamics, combined with coarse-grained molecular dynamics (Martini force field). These approaches allowed us to identify bona fide activation pathways and explore the topological constraints imposed by bis-phosphorylated peptide binding to both SH2 domains.
- R. Frankson et al., Cancer Res. 77 (2017) 5701−5705.
- M. Tartaglia et al., Am. J. Hum. Genet. 78 (2006) 279−290.
- P. Calligari et al., Comp Struct Biotech J 19 (2021) 6125-6139
| Role | Professor/PI |
|---|
