- Communication -

Volume 2

Special Issue
GCB'01

Full article

Molecular dynamics simulations on the free and complexed N-terminal SH2 domain of SHP-2

Karin Wieligmann^*, Luis Felipe Pineda De Castro and Martin Zacharias

Theoretische Biophysik, Institut für Molekulare Biotechnologie (IMB), Beutenbergstr.11, D-07745 Jena, Germany
^*corresponding author


Edited by E. Wingender; received December 18, 2001; revised and accepted March 27, 2002; published March 28, 2002

Abstract

Signal transduction events are often mediated by small protein domains such as SH2 (Src homology 2) domains that recognize phosphotyrosines (pY) and flanking sequences. In case of the SHP-2 receptor tyrosine phosphatase an N-terminal SH2 domain binds and inactivates the phosphatase (PTP) domain. The pY-peptide- binding site on the N-terminal SH2 domain does not overlap with the PTP binding region. Nevertheless, pY-peptide binding causes domain dissociation and phosphatase activation. Comparative multi-nanosecond molecular dynamics simulations on the N-SH2 domain in ligand-bound and free states have been performed to study the allosteric mechanism that leads to domain dissociation upon pY-peptide binding.

Significant ligand-dependent differences in the conformational flexibility of regions that are involved in SH2-PTP domain association have been observed. The results support a mechanism of signal transduction where SH2-peptide binding modulates the domain flexibility and reduces its capacity to fit into the entrance of the PTP catalytic domain of SHP-2.

Key words: allosteric conformational change, signal transducution, ligand-receptor binding, molecular dynamics, SH2 domains, SHP-2 phosphatase, conformational flexibility