title: Molecular dynamics simulations on the free and complexed N-terminal SH2 domain of SHP-2.
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.
authors.affiliation: Theoretische Biophysik, Institut für Molekulare Biotechnologie (IMB), Beutenbergstr. 11, D-07745 Jena, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Wieligmann
authors.forename: Luis Felipe
authors.initials: LF
authors.lastname: Pineda De Castro
authors.forename: Martin
authors.initials: M
authors.lastname: Zacharias
mesh_terms: D000494:Allosteric Regulation; D047908:Intracellular Signaling Peptides and Proteins; D008958:Models, Molecular; D011487:Protein Conformation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry*; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; D015398:Signal Transduction; D018909:src Homology Domains
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases