Defining the Structural Basis of Nicastrin Function

Sangram Sisodia, PhD
University of Chicago (Chicago, IL)
Year Awarded:
2011
Grant Duration:
July 1, 2011 to June 30, 2013
Disease:
Alzheimer's
Award Amount:
$150,000
Grant Reference ID:
A2011054
Award Type:
Standard
Award Region:
US Midwestern

Co-principal Investigators

Shohei Koide, PhD
University of Chicago

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.

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.

Research Updates

Dr. Sisodia’s and Dr. Koide’s team has examined the function of nicastrin (NCT) protein, a part of the gamma secretase complex. NCT is proposed to serve as a receptor that recognizes and pulls in many targets, including the APP protein, that are then processed by the rest of the complex. Over the past year, the team has discovered a novel domain in NCT that they believe is a “substrate recognition motif” (the part of the protein that specifically targets proteins to be pulled into the complex). Since this complex is responsible for creating toxic beta-amyloid after processing the APP protein, this exciting result offers significant support for the future development of novel gamma secretase modulators as therapeutics for AD.

Publications

Zhang X, Hoey RJ, Lin G, Koide A, Leung B, Ahn K, Dolios G, Paduch M, Ikeuchi T, Wang R, Li YM, Koide S, Sisodia SS. Identification of a tetratricopeptide repeat-like domain in the nicastrin subunit of ?-secretase using synthetic antibodies. Proc Natl Acad Sci U S A. 2012 May 29;109(22):8534-9. doi: 10.1073/pnas.1202691109. Epub 2012 May 14. PubMed PubMed Icon Google Scholar Icon