Introduction
History
Function
NF1 is a GTPase-activation protein that binds to RAS to increase the hydrolysis of GTP to GDP. This inactivates the cell signaling of Ras until another GTP can replace the GDP from the cytosol. NF1 and Ras binding is possible in only the of NF1. The mechanism is shown in figure 1 and displays the slow hydrolysis of GTP bound to Ras and the fast hydrolysis of GTP when bound to NF1.
Structure
NF1 is a protein dimer that exists in a and conformation. Each protomer contains a GRD, Sec14-PH, and a Gpex domain located on a HEAT N-C arm. Ras binds to the GRD site with Arg1276 being the critical residue for binding.
Closed conformation
In the , one protomer has its domains shifted due to a 130 degree rotation. That rotation places in an orientation that in the GRD site (Figure 3). Making sterically impossible in the
. The can exist naturally without any form of stabilization but will also fall back to the .
Zinc Stabilized
The of NF1 can be stabilized by a zinc ion to prevent the shift back to an . This binding is done between C1032, H1558, and H1576 within the N-HEAT domain, GRD-Sec14-PH linker L2 and is shown in figure 2. When zinc stabilizes, NF1 will stay in the and continue to inhibit the binding of RAS.
Open conformation
In the one protomer is shifted due to a 90 rotation. This rotation allows for binding between RAS and the
in the GRD site while in the . This means that the can occur without any steric hindrance as shown in the .
Conformational Change Linkers
Domains
Arginine 1276
Conformational Change Linkers
