Neurofibromin 2 Controls Tumor Growth via Its Dynamic Structural States
Abstract
Background: Patients with the inherited or sporadic mutations in the neurofibromatosis type 2 (NF2) gene develop a number of incurable neurological tumors, including schwannomas, meningiomas, and ependymomas, and they also can develop a malignant tumor in their lungs called mesothelioma. Further, young adults with inherited NF2 often have neurological or hearing deficits. The NF2 gene encodes for a protein termed neurofibromin 2 (or schwannomin or merlin for moesin-ezrin-radixin-like protein), which functions as a protein that links key cell surface receptors, called cadherins, that direct cell-cell contacts to the actin cytoskeleton of the cell. Notably, loss-of-function neurofibromin 2 mutants found in NF2 disrupt cell-cell contacts, provoking uncontrolled growth of these cells and, ultimately, development of NF2-associated malignancies. Rationale and Objectives: Development of effective, safe therapeutics that can be used to combat the incurable malignancies that are a hallmark of NF2 requires a detailed understanding of the molecular basis of this disease. Loss-of-function mutations of neurofibromin 2 are the hallmark of NF2. We recently solved the crystal structures of the human neurofibromin 2 N-terminal domain that are bound to the phospholipid PIP2 (manuscript under review). Interestingly, the lipid-bound structure suggests that attachment to the plasma membrane switches neurofibromin 2 to its open conformational state by folding the N-terminal extended a-helix of the N-terminal domain that is otherwise unstructured. Thus, we propose that the extended a-helix acts as a conformational sensor by mediating the open and closed conformers of neurofibromin 2. Clinical Applicability of the Proposed Research: The proposed studies focus on defining the structure of neurofibromin 2 in complex with key partners and determining how the neurofibromin 2 mutants that are found in NF2 affect these interactions. We submit that the proposed studies will eventually lay the groundwork for development of small molecule screens. Contributions to Advancing the Field of NF Research: It has recently become clear that the structure of neurofibromin 2 differs from the generally accepted model that is based on the structural and functional relationship of the ezrin, radixin, moesin proteins, underscoring the importance of structural studies of neurofibromin 2 in particular to understand its mechanism of activation. However, despite intensive efforts to obtain structural data on neurofibromin 2, only very limited data are available. The proposed studies will thus fill a void and determine the molecular details of several states of neurofibromin 2 bound to key binding partners. We submit that fully understanding the structure and function of neurofibromin 2 is necessary for the design and development of targeted therapeutics for treating NF2 patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810451
Entities
People
- Tina Izard
Organizations
- Scripps Research
- United States Army