Allosteric modulation of NF1 GAP activity

Authors

• L Xu
• H Jang
• R Nussinov

Abstract

Neurofibromin (NF1) functions as a tumor suppressor, regulating the GTP hydrolysis of Ras proteins. Mutations in the NF1 gene on chromosome 17 result in the development of a tumor, clinically referred to as neurofibromatosis type 1, which exhibits uncontrolled growth within the nervous system. Many missense mutations in the GAP-related domain (GRD) of NF1 are located away from the catalytic site. How these mutations affect NF1 GAP activity remains unclear. Furthermore, variants in the same location of the GRD show different phenotypes (neurofibromatosis or neurodevelopmental disorder), raising the tantalizing question of how these mutations drive different NF1 diseases. Here, we performed molecular dynamics simulations of the NF1 GRD in complex with Ras. Our simulation results confirmed the critical role of the arginine finger in the conformational transition from the ground state to the transition state during GTP-hydrolysis. In particular, we identified distinct ionic interactions at the binding interface between Ras and NF1 that could determine the consequence of those long-range mutations. We propose that different variants of the same residue may act through loss-of-function or gain-of-function, leading to different phenotypes. Such allosteric modulation of NF1 GAP activity is further demonstrated by the significantly reduced GAP activity of an alternative splice of NF1 exon 23a, which inserts 21 amino acids into the GRD of NF1. Taken together, our work delineates the molecular mechanism of how structural alterations on the NF1 GRD allosterically modulate its GAP activity and provides therapeutic insight into the development of small molecules that restore NF1 catalytic activity.

Scientific Focus Area: Molecular Biology and Biochemistry

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