Structural analysis of the GAP-related domain from neurofibromin and its implications

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Abstract
Neurofibromin is the product of the NF1 gene, whose alteration is responsible for the pathogenesis of neurofibromatosis type 1 (NF1), one of the most frequent genetic disorders in man. It acts as a GTPase activating protein (GAP) on Ras; based on homology to p120GAP, a segment spanning 250‐400 aa and termed GAP‐related domain (NF1GRD; 25‐40 kDa) has been shown to be responsible for GAP activity and represents the only functionally defined segment of neurofibromin. Missense mutations found in NF1 patients map to NF1GRD, underscoring its importance for pathogenesis. X‐ray crystallographic analysis of a proteolytically treated catalytic fragment of NF1GRD comprising residues 1198‐1530 (NF1‐333) of human neurofibromin reveals NF1GRD as a helical protein that resembles the corresponding fragment derived from p120GAP (GAP‐334). A central domain (NF1c) containing all residues conserved among RasGAPs is coupled to an extra domain (NF1ex), which despite very limited sequence homology is surprisingly similar to the corresponding part of GAP‐334. Numerous point mutations found in NF1 patients or derived from genetic screening protocols can be analysed on the basis of the three‐dimensional structural model, which also allows identification of the site where structural changes in a differentially spliced isoform are to be expected. Based on the structure of the complex between Ras and GAP‐334 described earlier, a model of the NF1GRD‐Ras complex is proposed which is used to discuss the strikingly different properties of the Ras‐p120GAP and Ras‐neurofibromin interactions.