BPCPPDYSOE21 – scientific programme

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BP: Fachverband Biologische Physik

BP 12: Single Molecule Biophysics I

BP 12.4: Talk

Tuesday, March 23, 2021, 10:10–10:30, BPa

Do the loops in the N-SH2 binding cleft truly serve as allosteric switch in SHP2 activation? A tale of disorder, crystal contacts, and activation free energies — Massimiliano Anselmi and •Jochen S Hub — Unvierstität des Saarlandes, Saarbrücken, Germany

SHP2 is a multi-domain protein, playing an important role in upregulating cellular processes such as cell survival, proliferation, and programmed cell death. SHP2 mutations cause developmental disorders and were found in many cancer types. In healthy cells, SHP2 mainly takes an autoinhibited, inactive form, and SHP2 is activated upon binding of a phosphopeptide to the N-SH2 domain. For the past two decades, the widening of the binding cleft upon peptide binding has been considered as the key event driving SHP2 activation.

We re-analyzed the manifold amount of crystallographic data of SHP2, and we carried out extensive MD simulations and free energy calculations of SHP2 in solution and in a crystal environment. We found that the "allosteric switch" model is in fact compromised by crystal contacts and flexible, poorly resolved loops, and that the degree of openness of the binding cleft does not even influence the free energy of SHP2 opening. Instead, we detected an alternative allosteric mechanism, namely the unzipping of a central beta sheet of N-SH2, which drives SHP2 activation. Apart from the implications on SHP2 activation and inhibition, the study highlights that MD simulations in crystal and solution environments are a powerful tool to avoid misinterpretation of crystal structures.