Structure of the Neurofibromatosis Type 1 Protein

Neurofibromatosis type 1 (NF1) is a genetic disease characterized by numerous symptoms including benign and malignant tumors of the nervous system, bone deformations, learning disabilities and others. The cellular bases of the disease are defects in a certain chromosome that carries the blueprint for a critical cellular protein molecule, called neurofibromin. This protein regulates processes important for a cell to become part of an organissue or to control cell proliferation. On translating the genetic information into protein the defects lead to errors in the protein architecture that negatively affect its normal cellular function and thus cause the disease. Understanding the protein function, its interactions with binding partners within the cell and how protein errors affect these interactions is critical for understanding disease defects and developing effective therapeutics against NF1. Of neurofibromin only the major signal regulatory function is biochemically well defined and established. We know the structure of the module responsible for that function and of another lipid binding module the function of which is currently unclear. About 75% of the neurofibromin structure is unknown. Knowledge of the whole neurofibromin structure is important to identify and characterize unknown functions of the protein and potentially new structural protein modules within the protein. Structural analysis of neurofibromin has been challenging because of the size and chemical properties of the protein and associated difficulties to prepare samples that can be used for structural analysis. As a ground work we have established preparation protocols that enable the application of high resolution structure determination techniques to neurofibromin and to a neurofibromin related protein derived from a fungus. We would like to use such samples to apply powerful electron microscopy and a technique called X- ray crystallography the latter of which requiring the protein in crystalline form. One of our samples fulfills this requirement. We hope at the end of our study to present the long awaited neurofibromin structure or one of its relatives. Such a structure would enable the detailed assessment of more than 100 single site alterations on the protein level and derive ideas how such alterations can be pathogenic. Defining the cellular consequences of single alterations could provide a rationale what measures to take to help those patients in the clinic. While our study will most probably not provide a compound for immediate NF1-treatment, it will likely shed functional light on the effect of some alterations found in NF1 patients and may thus lay the ground for later identification of drug targets and define therapeutic strategies at the level of basic cellular research.