Investigating the reason for loss-of-function of Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2) caused by Y279C mutation through molecular dynamics simulation. Issue 9 (12th June 2020)

• Record Type: Journal Article
• Authors: Liu, Wen-Shan; Wang, Rui-Rui; Li, Wei-Ya; Rong, Mei; Liu, Chi-Lu; Ma, Ying; Wang, Run-Ling
• Is Part Of: Journal of biomolecular structure & dynamics. Volume 38:Issue 9(2020)
• Page Start: 2509
• Page End: 2520
• Publication Date: 2020-06-12
• Subjects: NSML -- SHP2WT -- SHP2Y279C -- molecular dynamics simulation; Biomolecules -- Periodicals; Molecular structure -- Periodicals; Molecular Biology -- Periodicals; Biomechanics -- Periodicals; 572
• DOI: 10.1080/07391102.2019.1634641
• Languages: English
• ISSNs: 0739-1102

Abstract

Abstract: Noonan syndrome with multiple lentigines (NSML), formerly known as LEOPARD syndrome (LS), is an autosomal dominant inherited multisystemic disorder. Most patients involve mutation in SHP2 encoded by tyrosine-protein phosphatase non-receptor type 11 (PTPN11) gene. Studies have shown that NSML-associated Y279C mutation exhibited the reduced phosphatase activity, leading to loss-of-function (LOF) of SHP2. However, the effect of the Y279C mutation on the SHP2 at the molecular level is unclear. In this study, molecular dynamics simulations of SHP2 wild-type (SHP2 WT ) and Y279C mutant (SHP2 Y279C ) were performed to investigate the structural differences in proteins after Y279C mutation and to find out the reason for loss-of-function of SHP2. Through a series of post-dynamic analyses, it was found that the protein occupied a smaller phase space after Y279C mutation, showing reduced flexibility. Specifically, due to the mutation of Y279C, the secondary structures of these two regions (residues Lys70-Ala72 and Gly462-Arg465) were significantly transformed from Turn to α-helix and β-strand. Furthermore, by calculating the residue interaction network, hydrogen bond occupancy and binding free energy, it was further revealed that the conformational differences between SHP2 WT and SHP2 Y279C systems were mainly caused by the differences in the interaction between Arg465–Phe469, Ile463–Gly467, Cys279–Lys70, Cys459–Ala72, Gly464–Phe71, Phe71–Ile463, Ile463–Ala505 and Arg465–Glu361. Consequently, this finding is expected to provide a new insight into the reason for loss-of-function of SHP2 caused by Y279C mutation. Communicated by Ramaswamy H. Sarma