Area di Ricerca Genetica e Malattie Rare, Bambino Gesù Children's Hospital, IRCCS, Piazza S. Onofrio 4, 00165 Rome, Italy.
Int J Mol Sci. 2022 Apr 27;23(9):4794. doi: 10.3390/ijms23094794.
The localization and activity of the SHP2 tyrosine phosphatase across different cellular compartments to the target substrates are steered by the binding of phosphotyrosine (pY) peptides to the tandem SH2 domains. The most N-terminal domain (N-SH2) can also keep the enzyme inactive by intramolecular occlusion of the catalytic site. Enzyme activity can be recovered by an allosteric disruption of this self-inhibitory docking upon the binding of pY peptides to the N-SH2 domain. Prior to this, the N-SH2 domain must abandon the closed conformation because it impedes the access of pY peptides to the binding cleft. Although it cooperates with the self-inhibitory docking in the negative regulation of the phosphatase activity, the structural determinants of the stability of the closed conformation in the self-inhibited phosphatase are still elusive. To address this issue, a molecular dynamics simulation study is carried out. It is shown that the closed conformation is stabilized by the interaction of the N-SH2 domain with a conserved peptide portion in the region encoded by exon 6 (E6).
SHP2 酪氨酸磷酸酶在不同细胞区室中的定位和活性，以及其对靶底物的作用，是由磷酸酪氨酸 (pY) 肽与串联 SH2 结构域的结合来控制的。最 N 端的结构域 (N-SH2) 也可以通过催化位点的分子内封闭使酶保持无活性。当 pY 肽与 N-SH2 结构域结合时，这种自我抑制对接的变构破坏可以恢复酶的活性。在此之前，N-SH2 结构域必须放弃封闭构象，因为它阻碍了 pY 肽进入结合裂隙。尽管它与自我抑制对接共同作用，对磷酸酶活性的负调控，但自我抑制磷酸酶中封闭构象稳定性的结构决定因素仍然难以捉摸。为了解决这个问题，进行了一项分子动力学模拟研究。结果表明，封闭构象通过 N-SH2 结构域与外显子 6 (E6) 编码区域中保守肽段的相互作用得到稳定。
