Structural Basis of FAD Mutations Within the Transmembrane Domain of APP

This project aims to define the structural characteristics of trans-membrane portion of Amyloid Precursor Protein (APPTM) as a gamma-secretase substrate that plays a role in determining the amyloid beta 42/amyloid beta 40 ratio. This will be achieved by combining a gamma-secretase assay and structural determination of normal and a variety of mutant forms of APPTM.

Understanding the generation of amyloid beta by a key enzyme, gamma-secretase is critical for developing disease-modifying treatment of Alzheimer’s disease. Although intense efforts are devoted to the structural biology of gamma-secretase, little attention is paid to the substrate of gamma-secretase, the transmembrane domain of the amyloid precursor protein (APPTM). This project will study the 3D structures of APPTM and their relevance to the generation of the more toxic form of amyloid beta. Understanding the structural determinants of the substrate will generate great insight to the development of Alzheimer’s disease and for designing gamma-secretase inhibitors and modulators.

We will 1) solve the structure of APPTM and 2) correlate structural characteristics of APPTM with properties in amyloid beta production.

Progress Updates

A transmembrane domain is a part of a protein that helps to anchor it into the correct locations in the cell so that it can perform its function. Dr. Chunyu Wang and collaborators aimed to define the structure of the transmembrane portion of the Amyloid Precursor Protein, called APPTM. Knowing the structure of APPTM will help to define how gamma‐secretase binds to and digests APP, which in turn will determine the ratio of toxic beta‐amyloid 42 fragments to the less toxic beta‐amyloid 40 fragments. These researchers successfully produced protein samples of a normal APPTM and an Alzheimer’s disease (AD)‐causing mutant and have collected high quality structural data with a method called “solution nuclear magnetic resonance.” These data provide important insight into the basic mechanisms of beta-amyloid generation and AD.