Structure and Functional Analysis of Nicastrin

Summary

Gamma-secretase is a complex of membrane proteins consisting of presenilin 1 or presenilin 2 (PS1 or PS2), APH-1, nicastrin (NCT) and PEN-2. It is now certain that PS serves as the catalytic center of the complex, but our understanding of the roles of the individual components in promoting gamma-secretase activity is still limited. We have chosen to examine NCT, a molecule proposed to serve as a receptor that facilitates engagement of the substrate with the catalytic site. The central aim of our study is to understand the structure and function of NCT with the notion that we will gain insights into the differential recognition of substrates, information that will be of immense interest in academic and pharmaceutical interests that are focused on the development of novel gamma secretase modulators as therapeutics for AD.

Project Details

Beta‐amyloid, the sticky protein that is the main component of brain plaques in Alzheimer's disease, is created by clipping it from a bigger protein, called beta‐amyloid precursor protein (APP). This clipping of APP is done by gamma secretase, a bundle of proteins that includes presenilin 1 or 2, APH‐1, PEN‐2, and nicastrin (NCT). NCT is the part of the bundle that recognizes and pulls into the complex many of the proteins, including APP, that are then processed by the rest of the gamma secretase proteins. Drs. Sangram Sisodia, Shohei Koide, and collaborators will study the shape of NCT to better understand how it partners with other proteins. They will make antibodies that bind like a lock and key to different parts of NCT to aid in their analysis. Once the shape of NCT is determined, the next step will be to design and test new drugs to specifically block NCT from binding to APP and, as a result, prevent the creation of beta‐amyloid.