Cryo-EM of ABCA4 and Correction in Macular Degeneration Defects
Co-Principal InvestigatorsAlecia K. Gross, PhD
A critical part of our visual process is the recycling of a special molecule called a chromatophore after exposure to light by a molecular pump that allows the cell to regenerate the active form of the chromatophore. Some diseases of the eye result in misfolding and malfunction of the pump, called ABCA4, which can eventually lead to blindness. We propose to determine the three-dimensional structure of the active form of ABCA4, as well as to develop a drug selection process to discover new drugs that can correct folding defects of the ABCA4 pump. Our work may likely allow new FDA-approved treatments for visual diseases such as macular degeneration.
The goal of this project is to better understand the mechanism of the ABCA4 pump involved in vision, and to correct defects of the pump for treating diseases in macular degeneration (MD). Certain molecules in the visual process need to be regenerated and recycled when they are exposed to light. ABCA4 works just like a molecular pump and is involved in recycling an important light-sensitive molecule call retinal. In Aim1, we proposed to determine the structure of the ABCA1 protein in its dimeric state, which very likely represents the active form of the pump. To date, no complete autonomous pump that utilizes the energy from ATP of any protein family in the human genome has been determined in a dimeric configuration. In Aim2, we will adapt our drug screening assay previously used for Cystic Fibrosis to identify novel compounds that could be developed into drugs for treating problems in vision related to defecting ABCA1 folding. Each aim is very innovative because no dimeric configuration of ABCA1 has been described, and no yeast-based assay using protein folding readout has been applied to ABCA1 in the visual process. Our work could allow identification of new drugs to treat MD through the processes of drug screening and cutting-edge rational drug design.