Gain-of-Function SHP2 E76Q Mutant Rescuing Autoinhibition Mechanism Associated with Juvenile Myelomonocytic Leukemia

Juvenile myelomonocytic leukemia (JMML) is an invasive myeloproliferative neoplasm and is a childhood disease with very high clinical lethality. The SHP2 is encoded by the PTPN11 gene, which is a nonreceptor (pY)-phosphatase and mutation causes JMML. The structural hierarchy of SHP2 includes protein tyrosine phosphatase domain (PTP) and Src-homology 2 domain (N-SH2 and C-SH2). Somatic mutation (E76Q) in the interface of SH2-PTP domain is the most commonly identified mutation found in up to 35% of patients with JMML. The mechanism of this mutant associated with JMML is poorly understood. Here, molecular dynamics simulation was performed on wild-type and mutant (E76Q) of SHP2 to explore the precise impact of gain-of-function on PTP's activity. Consequently, such impact rescues the SHP2 protein from autoinhibition state through losing the interface interactions of Q256/F7 and S502/Q76 or weakening interactions of Q256/R4, Q510/G60, and Q506/A72 between N-SH2 and PTP domains. The consequences of these interactions further relieve the D'E loop away from the PTP catalytic site. The following study would provide a mechanistic insight for better understanding of how individual SHP2 mutations alter the PTP's activity at the atomic level.

[1]  B. Neel,et al.  The tyrosine phosphatase Shp2 (PTPN11) in cancer , 2008, Cancer and Metastasis Reviews.

[2]  C. Walsh,et al.  Potent Stimulation of SH-PTP2 Phosphatase Activity by Simultaneous Occupancy of Both SH2 Domains (*) , 1995, The Journal of Biological Chemistry.

[3]  Ray Luo,et al.  New Force Field on Modeling Intrinsically Disordered Proteins , 2014, Chemical biology & drug design.

[4]  J. Contreras-Garcı́a,et al.  Accurately extracting the signature of intermolecular interactions present in the NCI plot of the reduced density gradient versus electron density. , 2017, Physical chemistry chemical physics : PCCP.

[5]  Tian Lu,et al.  Multiwfn: A multifunctional wavefunction analyzer , 2012, J. Comput. Chem..

[6]  Flavio Seno,et al.  Geometry and symmetry presculpt the free-energy landscape of proteins. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[7]  A. Rehman,et al.  The Landscape of Protein Tyrosine Phosphatase (Shp2) and Cancer. , 2019, Current pharmaceutical design.

[8]  T. Pawson,et al.  Phosphotyrosine phosphatases with SH2 domains: regulators of signal transduction. , 1994, Trends in genetics : TIG.

[9]  G. Ciccotti,et al.  Numerical Integration of the Cartesian Equations of Motion of a System with Constraints: Molecular Dynamics of n-Alkanes , 1977 .

[10]  Duncan Poole,et al.  Routine Microsecond Molecular Dynamics Simulations with AMBER on GPUs. 2. Explicit Solvent Particle Mesh Ewald. , 2013, Journal of chemical theory and computation.

[11]  S. Shoelson,et al.  Crystal Structure of the Tyrosine Phosphatase SHP-2 , 1998, Cell.

[12]  Julia Contreras-García,et al.  Revealing noncovalent interactions. , 2010, Journal of the American Chemical Society.

[13]  Sarah A. Teichmann,et al.  Relative Solvent Accessible Surface Area Predicts Protein Conformational Changes upon Binding , 2011, Structure.

[14]  Xiu-Bo Chen,et al.  The design of novel inhibitors for treating cancer by targeting CDC25B through disruption of CDC25B-CDK2/Cyclin A interaction using computational approaches , 2017, Oncotarget.

[15]  B. Neel,et al.  The 'Shp'ing news: SH2 domain-containing tyrosine phosphatases in cell signaling. , 2003, Trends in biochemical sciences.

[16]  Sarah L. Williams,et al.  Dual Allosteric Inhibition of SHP2 Phosphatase. , 2018, ACS chemical biology.

[17]  Malcolm McGregor,et al.  Diverse Biochemical Properties of Shp2 Mutants , 2005, Journal of Biological Chemistry.

[18]  G. Feng,et al.  PTPN11 is the first identified proto-oncogene that encodes a tyrosine phosphatase. , 2007, Blood.

[19]  C. Walsh,et al.  Activation of the SH2-containing protein tyrosine phosphatase, SH-PTP2, by phosphotyrosine-containing peptides derived from insulin receptor substrate-1. , 1994, The Journal of biological chemistry.

[20]  S. Kondo,et al.  Isolation of a distinct class of gain-of-function SHP-2 mutants with oncogenic RAS-like transforming activity from solid tumors , 2008, Oncogene.

[21]  Asimul Islam,et al.  A review of methods available to estimate solvent-accessible surface areas of soluble proteins in the folded and unfolded states. , 2014, Current protein & peptide science.

[22]  Tian Lu,et al.  Quantitative analysis of molecular surface based on improved Marching Tetrahedra algorithm. , 2012, Journal of molecular graphics & modelling.

[23]  Hui Zhou,et al.  Exploring the reason for increased activity of SHP2 caused by D61Y mutation through molecular dynamics , 2019, Comput. Biol. Chem..

[24]  H. Gohlke,et al.  Free Energy Calculations by the Molecular Mechanics Poisson−Boltzmann Surface Area Method , 2012, Molecular informatics.

[25]  Michael A. Patton,et al.  Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome , 2001, Nature Genetics.

[26]  Ashfaq Ur Rehman,et al.  Exploring the Pyrazinamide Drug Resistance Mechanism of Clinical Mutants T370P and W403G in Ribosomal Protein S1 ofMycobacterium tuberculosis , 2019, J. Chem. Inf. Model..

[27]  Qifeng Bai,et al.  Investigation of allosteric modulation mechanism of metabotropic glutamate receptor 1 by molecular dynamics simulations, free energy and weak interaction analysis , 2016, Scientific Reports.

[28]  P. Kollman,et al.  Calculating structures and free energies of complex molecules: combining molecular mechanics and continuum models. , 2000, Accounts of chemical research.

[29]  T. Darden,et al.  Particle mesh Ewald: An N⋅log(N) method for Ewald sums in large systems , 1993 .

[30]  A. Liwo,et al.  Principal component analysis for protein folding dynamics. , 2009, Journal of molecular biology.

[31]  H. Heng,et al.  Receptor-binding, tyrosine phosphorylation and chromosome localization of the mouse SH2-containing phosphotyrosine phosphatase Syp. , 1994, Oncogene.

[32]  R. Dror,et al.  Improved side-chain torsion potentials for the Amber ff99SB protein force field , 2010, Proteins.