Characterization of de novo missense variants in individuals with neurodevelopment disorders and their impact on the structure and function of the protein SHP2

L. Martínek1, P. Havlíčková2, Z. Futera3, M. Fencková1

1Department of Molecular Biology and Genetics, Faculty of Science, University of South Bohemia, České Budějovice

2Department of Chemistry, Faculty of Science, University of South Bohemia, České Budějovice

3Department of Physics, Faculty of Science, University of South Bohemia, České Budějovice

martil16@prf.jcu.cz

SHP2 is a protein-tyrosine phosphatase encoded by the gene PTPN11. It is a positive regulator of RAS-MAPK signalling pathway, which is important for cell division. Deregulation of the pathway can lead to cancer or severe neurodevelopmental disorders (NDD) [1]. Therefore, it needs to be tightly controlled. SHP2 controls RAS-MAPK by dephosphorylating its inhibitor Sprouty1 [2]. Most disease-causing variants in PTPN11 are gain of function, which means, that SHP2 more efficiently dephosphorylates its substrates [3]. My work focuses on the novel, uncharacterized variants identified in individuals with NDD. These variants are missense and result in single amino acid substitutions.

SHP2 is composed of three domains: N-SH2 domain, C-SH2 domain and PTP-domain (catalytic domain) and can be present in two conformations – inactive state and active state. In the inactive state, N-SH2 domain interacts with the PTP-domain and disables its dephosphorylation activity. This process is called autoinhibition.  To become active, a binding protein needs to provide tyrosine phosphates to the N-SH2 and C-SH2 domains. This stops the autoinhibition and the PTP-domain is accessible and can dephosphorylate its substrates [3]. My aim is to investigate the impact of the novel missense variants on the autoinhibition process with the use of molecular dynamics. The results will help to elucidate their pathogenicity and their effect on molecular function. The gained knowledge will be utilized for the selection of the most effective SHP2-targeting drugs from existing libraries or for design of new drugs that are specific to these variants.

1.         Krab, L., C., et al. (2008) Oncogenes on my mind: ERK and MTOR signaling in cognitive diseases, Trends in Genetics; 24: 499-510.

2.         Morrison, D., K. (2012) MAP Kinase Pathways, Cold Spring Harb Perspect Biol.

3.         Yu, Z., H., et al. (2014) Molecular basis of gain-of-function LEOPARD syndrome-associated SHP2 mutations. Biochemistry; 53: 4136-4151.

This work is supported by the Czech Grant Agency (grant no. 23-07810S) and by the ERC-CZ program of the Ministry of Education, Youth and Sports (grant no. LL2322)