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.

Rizza, F., Vertemara, J., & Tisi, R. (2022). Molecular Dynamics Simulations Reveal Structural Interconnections within Sec14-PH Bipartite Domain from Human Neurofibromin. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 23(10) [10.3390/ijms23105707].

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

Rizza, Fabio
Primo
;
Vertemara, Jacopo
Secondo
;
Tisi, Renata
Ultimo
2022

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.
Articolo in rivista - Articolo scientifico
cancer-prone syndrome; MD; neuropathy; NF1;
English
Rizza, F., Vertemara, J., & Tisi, R. (2022). Molecular Dynamics Simulations Reveal Structural Interconnections within Sec14-PH Bipartite Domain from Human Neurofibromin. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 23(10) [10.3390/ijms23105707].
Rizza, F; Vertemara, J; Tisi, R
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/377068
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