Introduction

Neurofibromin is a protein that is coded for by the NF1 gene which is located on chromosome 17. It functions as a tumor suppressor gene through its association with the protein Ras.

Structure

Neurofibromin is a homodimer made up of two identical chains. There are two conformations that classify neurofibromin known as its open and closed conformations. These conformations allow neurofibromin to associate with the protein Ras and perform its function of Ras regulation. The transformation between the overall closed conformation and open conformation of neurofibromin signifies a transition between an active neurofibromin protein and an inactive neurofibromin protein. There are two important domains involved in the transition between the open and close conformations, the GRD and the Sec14-PH domain. Although neurofibromin is a homodimer with two identical protomers, only one protomer needs to have its GRD and Sec14-PH domains rotated in the open conformation in order for it to be able to perform its function.

Closed Conformation

Open Conformation

Function

Neurofibromin functions as a tumor suppressor protein. Its job is to prevent cell growth by turning off another protein known as Ras which in its active state, stimulates cell growth and division. Ras is a GTPase membrane protein that can only interact with Neurofibromin, a cytoplasmic protein, in the open conformation. As Neurofibromin is a cytoplasmic protein, it is brought to the membrane to associate with Ras via another protein known as SPRED1. Neurofibromin can interact with SPRED1 in both the open and closed conformations however, it can only associate with Ras when it is in its open conformation. The interaction between Neurofibromin and Ras occurs via an arginine finger (R1276) present in the GRD of Neurofibromin which is critical for Ras binding. R1276 is only accessible for binding when the GRD and Sec14-PH domains of Neurofibromin are rotated into the open conformation and there is no steric hindrance from the surrounding dimer chains. When R1276 is able to associate with Ras, Neurofibromin downregulates the Ras signaling pathway by hydrolyzing the GTP associated with Ras to GDP, effectively making it inactive and inhibiting cell growth and division.

Disease

Student Contributors

• Hannah Luchinski
• Sophie Mullinix

Structural highlights

This is a sample scene created with SAT to by Group, and another to make of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.