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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.

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