Molecular Dynamics Simulations Reveal Structural Interconnections within Sec14-PH Bipartite Domain from Human Neurofibromin

Fabio Rizza; Jacopo Vertemara; Renata Tisi

doi:10.3390/ijms23105707

Molecular Dynamics Simulations Reveal Structural Interconnections within Sec14-PH Bipartite Domain from Human Neurofibromin

Int J Mol Sci. 2022 May 20;23(10):5707. doi: 10.3390/ijms23105707.

Authors

Fabio Rizza¹, Jacopo Vertemara¹, Renata Tisi^{1

2}

Affiliations

¹ Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126 Milan, Italy.
² Milan Center for Neuroscience (NeuroMI), University of Milano-Bicocca, 20126 Milano, Italy.

Abstract

Neurofibromin, the main RasGAP in the nervous system, is a 2818 aa protein with several poorly characterized functional domains. Mutations in the NF1-encoding gene lead to an autosomal dominant syndrome, neurofibromatosis, with an incidence of 1 out of 3000 newborns. Missense mutations spread in the Sec14-PH-encoding sequences as well. Structural data could not highlight the defect in mutant Sec14-PH functionality. By performing molecular dynamics simulations at different temperatures, we found that the lid-lock is fundamental for the structural interdependence of the NF1 bipartite Sec14-PH domain. In fact, increased flexibility in the lid-lock loop, observed for the K1750Δ mutant, leads to disconnection of the two subdomains and can affect the stability of the Sec14 subdomain.

Keywords: MD; NF1; cancer-prone syndrome; neuropathy.

MeSH terms

Genes, Neurofibromatosis 1
Humans
Infant, Newborn
Molecular Dynamics Simulation
Neurofibromatosis 1* / genetics
Neurofibromin 1* / genetics
Pleckstrin Homology Domains

Substances

Neurofibromin 1

Grants and funding

F.R. was supported by a Ph.D. fellowship from the Italian Ministry of University and Research (MIUR); J.V. was supported by a post-doc fellowship from the Italian Ministry of University and Research (MIUR). Access to the high-performance computing resource MARCONI, on which all molecular dynamics simulations have been run, was granted by ‘Consorzio Interuniversitario del Nord-Est per il Calcolo Automatico’ (CINECA) to the University of Milano-Bicocca.