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Function
Disease
Relevance
Structure
Neurofibromin is a large protein of 2818 amino acids [3] and is a homodimer that exists in two conformations.
Domains
Neurofibromin consists of multiple domains: N-HEAT/ARM, GRD, Sec14-PH, GAPEx, and C-HEAT/ARM. The two most characterized domains of neurofibromin are the Sec14-PH and GRD domains. Each of the protomers of neurofibromin contains these domains.
The N-HEAT/ARM and C-HEAT/ARM are rigid, which makes them critical in the rearrangement of the Gap-related and Sec14-PH domains. In the closed conformation, the HEAT/ARM domains cover the GRD, preventing the binding of Ras through steric hinderance. The HEAT/ARM cores are made up of many alpha helices. [4]
conformations
closed
The closed state of neurofibromin has both protomers in a closed conformation, which inhibits the binding of Ras to the GRD of neurofibromin due to the HEAT/ARM blocking the GRD. A metal binding site between the N-HEAT/ARM domain and the GRD-Sec14-PH linker stabilize the closed conformation. This site is coordinated by three residues, C1032, H1558, and H1576, and a water molecule. This binding site is preferential for zinc.
open
The open state of neurofibromin has one protomer in a open conformation and the other in a closed conformation. The protomer in the open conformation allows for the binding of Ras because of reorientation of the GRD and Sec14-PH domains. In the open conformation, the metal binding site found in the closed conformation is lost due to separation of the N-HEAT/ARM and the cysteine residue from the histidine residues founds in the GRD-Sec14-PH linker.
transition between open and closed conformation
rearrangement of connective loops between domains
triad of residues from nf
GAPex
Spred1
CSRD and CTD
The Cysteine-Serine-rich domain (CSRD) and C-terminal domain (CTD) contain phosphorylation sites. The CSRD is able to be phosphorylated by protein kinases A and C Phosphorylation by protein kinase C is a positive regulator of neurofibromin activity. The CTD is phosphorylated primarily by protein kinase C. This domain is a negative regulator of neurofibromin activity if particular residues are phosphorylated. CTD contains a nuclear localization signal as well.
