Cellular signalling is the process by which cells sense their environment and respond accordingly. This process is coordinated by a complex machinery of molecules, and its faulty regulation can arise in, and cause a plethora of human diseases. One such disease is neurofibromatosis type I, a genetic disorder caused exclusively by mutations in the gene NF1, and is characterized by dermatological and neurological symptoms, as well as predisposition to cancers.

The NF1 gene encodes a large signalling protein called neurofibromin, a negative regulator of the small cancer-associated protein Ras. To accomplish its Ras-inhibiting activity, neurofibromin uses a small domain located at the centre of its sequence. However, this catalytic domain constitutes only about 10% of the total mass of the protein and it is flanked by large region of unknown function. Nevertheless, we know that these regions are essential in neurofibromin function given that single mutations within these regions are sufficient to cause neurofibromatosis type I.

To better understand the role of these regions, and neurofibromin regulation as a whole, we determined its structure using an emerging structure determination technique called cryo-electron microscopy. Using this technique, we were able to visualize neurofibromin at near-atomic detail, revealing that neurofibromin forms a dimer reminiscent of an “infinity symbol” Further investigation revealed that neurofibromin can adopt two states: an opened/active state and closed/inactive state. The equilibrium between these two states and therefore regulation of neurofibromin activity is modulated by the presence of specific small molecules from cellular metabolism.

Taken together, our results have shown that neurofibromin is acting as a regulated on/off switch to Ras responding to the metabolic state of the cell. This finding deepens our understanding of neurofibromin regulation and may help to formulate better treatment for people afflicted with neurofibromatosis type I or other Ras-associated disease, notably cancers. We reported our work in a publication in Molecular Cell in 2022, Chaker-Margot et al.

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