Structural Insights into the Binding of Neurofibromin 2 to the Plasma Membrane
Abstract
Rationale and Objective: Mutations in the tumor suppressor protein termed neurofibromin 2 (aka schwannomin or merlin for moesinezrin-radixin-like protein) are responsible for Neurofibromatosis Type 2 (NF2). Neurofibromin 2 links key cell surface receptors, termed cadherins, which direct cell-cell contacts to the actin cytoskeleton of the cell. Loss-of-function mutations in neurofibromin 2 are found in NF2 that disrupt these cell-cell contacts, which results in uncontrolled growth of these cells and the development of NF2-associated malignancies. Here we seek to determine the structural mechanisms of neurofibromin 2 attachment to the cell membrane to exert its cell growth-inhibiting functions. Who Will It Help and How Will It Help: this research initially and directly will help patients with NF2 tumors. The disease is inherited and causes certain peripheral and central nerve cells to multiply in an uncontrollable fashion and become a tumor. Neurofibromin 2, which attaches to the surface of the cell, prevents these cells from losing control. It is believed that, when the structure of the protein is disrupted, the process of tumor formation begins. Our studies will define the active and disrupted structure of neurofibromin 2. The findings would aid the development of small molecules that might reactivate neurofibromin 2 functions in NF2 patients. Potential Clinical Applications, Benefits, and Risks: There are few structural studies in the field of NF. Our proposed studies will be pivotal and have significant impact on NF research in at least two ways: (1) technically, by our development of tools to determine the high-resolution structure of full-length neurofibromin 2 and (2) mechanistically, by providing structural insight into how neurofibromin 2 attaches to the plasma membrane to exert its cell growth-inhibiting functions. Essentially, it is the key step required for the nonsurgical treatment, whichever direction that may take. Such studies are long overdue and might lay the foundation for developing high-throughput assays that monitor neurofibromin 2 interaction and identifying small molecules that can reactivate neurofibromin 2 functions in NF2 patients. This study establishes no risk to patients, only opportunity for benefit. Projected Time Required to Achieve a Patient-Related Outcome: The proposed studies can be carried out within the 2-year timeframe that funding is requested, but will require follow-up studies to achieve a patient-related outcome. Likely Contributions of the Proposed Research Project to Advancing the Field of NF Research and/or Patient Care: The data obtained from this study could provide critical information needed in (1) synthesizing a vaccine to prevent the disease or (2) creating a molecular agent capable of correcting the dysfunctional protein in the NF Type 2 and returning it to its normal structure and function.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910418
Entities
People
- Tina Izard
Organizations
- Scripps Research
- United States Army