Structural Determinants for Bri2 Inhibition of A-Beta Production

This project seeks to determine the molecular structure of BRI2, a molecule that protects APP from being cleaved to produce amyloid beta. By comparing the structure of BRI2 when it is free to its structure when bound to APP, this study will highlight components of the protein that might serve as targets in future drug design.

The main protein that leads to Alzheimer’s disease (called A-beta) is only a small portion of a larger protein that has to be cut into smaller pieces to be toxic. One way to avoid building up the levels of the toxic piece, is to prevent its parent protein from being cut. Several researchers are working on inhibitors of that cutting enzyme. But there’s a problem — that enzyme is needed to cut other important proteins in the cell into their active form. Two groups recently found a new protein called BRI2 that only binds to the parent protein, and protects it from getting cut. One group has isolated the smallest piece of this BRI2 protein that does the job, and would like to modify it to use it as a drug to prevent build-up of the toxic A-beta, but they don’t know what makes it bind tightly and specifically to the A-beta parent protein. So, we are going to use a technique called Nuclear Magnetic Resonance (NMR) to get a detailed picture of that piece of the BRI2 protein alone (in Aim 1), and when it is bound to the A-beta parent protein (in Aim 2 and 3). This will tell the drug designers what parts of the protein need to be kept (or improved) for good binding to the target, and what parts can be changed to make the molecule a better drug. Hopefully this will lead to a drug that keeps down the levels of the toxic A-beta protein, but doesn’t have any side effects.