PMID- 31258001
OWN - NLM
STAT- MEDLINE
DCOM- 20210618
LR  - 20220531
IS  - 1538-0254 (Electronic)
IS  - 0739-1102 (Linking)
VI  - 38
IP  - 9
DP  - 2020 Jun
TI  - 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.
PG  - 2509-2520
LID - 10.1080/07391102.2019.1634641 [doi]
AB  - 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 alpha-helix and beta-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.
FAU - Liu, Wen-Shan
AU  - Liu WS
AD  - School of Pharmacy, Tianjin Key Laboratory on Technologies Enabling Development 
      of Clinical Therapeutics and Diagnostics (Theranostics), Tianjin Medical 
      University, Tianjin, China.
FAU - Wang, Rui-Rui
AU  - Wang RR
AD  - School of Pharmacy, Tianjin Key Laboratory on Technologies Enabling Development 
      of Clinical Therapeutics and Diagnostics (Theranostics), Tianjin Medical 
      University, Tianjin, China.
FAU - Li, Wei-Ya
AU  - Li WY
AD  - School of Pharmacy, Tianjin Key Laboratory on Technologies Enabling Development 
      of Clinical Therapeutics and Diagnostics (Theranostics), Tianjin Medical 
      University, Tianjin, China.
FAU - Rong, Mei
AU  - Rong M
AD  - School of Pharmacy, Tianjin Key Laboratory on Technologies Enabling Development 
      of Clinical Therapeutics and Diagnostics (Theranostics), Tianjin Medical 
      University, Tianjin, China.
FAU - Liu, Chi-Lu
AU  - Liu CL
AD  - School of Pharmacy, Tianjin Key Laboratory on Technologies Enabling Development 
      of Clinical Therapeutics and Diagnostics (Theranostics), Tianjin Medical 
      University, Tianjin, China.
FAU - Ma, Ying
AU  - Ma Y
AD  - School of Pharmacy, Tianjin Key Laboratory on Technologies Enabling Development 
      of Clinical Therapeutics and Diagnostics (Theranostics), Tianjin Medical 
      University, Tianjin, China.
FAU - Wang, Run-Ling
AU  - Wang RL
AD  - School of Pharmacy, Tianjin Key Laboratory on Technologies Enabling Development 
      of Clinical Therapeutics and Diagnostics (Theranostics), Tianjin Medical 
      University, Tianjin, China.
LA  - eng
PT  - Journal Article
DEP - 20190701
PL  - England
TA  - J Biomol Struct Dyn
JT  - Journal of biomolecular structure & dynamics
JID - 8404176
RN  - EC 3.1.3.48 (PTPN11 protein, human)
RN  - EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 11)
SB  - IM
MH  - Humans
MH  - Hydrogen Bonding
MH  - *LEOPARD Syndrome
MH  - *Molecular Dynamics Simulation
MH  - Mutation
MH  - Protein Structure, Secondary
MH  - Protein Tyrosine Phosphatase, Non-Receptor Type 11/*genetics
OTO - NOTNLM
OT  - NSML
OT  - SHP2WT
OT  - SHP2Y279C
OT  - molecular dynamics simulation
EDAT- 2019/07/02 06:00
MHDA- 2021/06/22 06:00
CRDT- 2019/07/02 06:00
PHST- 2019/07/02 06:00 [pubmed]
PHST- 2021/06/22 06:00 [medline]
PHST- 2019/07/02 06:00 [entrez]
AID - 10.1080/07391102.2019.1634641 [doi]
PST - ppublish
SO  - J Biomol Struct Dyn. 2020 Jun;38(9):2509-2520. doi: 
      10.1080/07391102.2019.1634641. Epub 2019 Jul 1.