Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

This Article Full Text (PDF, 898K) PPT slides of all figures Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Williams, R. Search for Related Content PubMed Articles by Williams, R. Related Collections Related Article Social Bookmarking                            What's this?

Stalling secretase assembly

Nicastrin binds other -secretase components when it is not binding Rer1p (right).

Alzheimer's disease might be slowed by inhibiting -secretase, the membrane protease complex that cleaves amyloid precursor protein (APP). Spasic et al. (page 629) now identify an endogenous inhibitor that prevents -secretase complex assembly and activity and thus might be targeted for therapy.

APP cleavage by -secretase leads to amyloid plaque deposition, one possible cause of Alzheimer's symptoms. -secretase is composed of four proteins—presenilin, nicastrin, PEN-2, and APH-1—which must come together for cleavage activity.

Although all four components are present in the ER, their assembly into functional -secretase is somehow restricted; most of the active enzyme is found close to the cell surface. Assembly of -secretase begins with the binding of nicastrin to APH-1. This binding, Spasic and colleagues now find, is prevented early in the secretion pathway by Rer1p, a membrane receptor that retrieves proteins from the Golgi back to the ER. Rer1p binds to nicastrin, thus interfering with nicastrin's ability to bind APH-1. Decreasing the amount of Rer1p led to an increase in -secretase activity.

Exactly what triggers Rer1p to release nicastrin and allow it to bind to APH-1, and subsequently to the other -secretase components, remains to be determined. Preventing this release might provide a means to reduce -secretase activity and thus amyloid plaque formation.

Ruth Williams

ruth.williams{at}rockefeller.edu

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

Related Article

Rer1p competes with APH-1 for binding to nicastrin and regulates -secretase complex assembly in the early secretory pathway

Dragana Spasic, Tim Raemaekers, Katleen Dillen, Ilse Declerck, Veerle Baert, Lutgarde Serneels, Joachim Füllekrug, and Wim Annaert
J. Cell Biol. 2007 176: 629-640. [Abstract] [Full Text] [PDF]

This Article Full Text (PDF, 898K) PPT slides of all figures Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Williams, R. Search for Related Content PubMed Articles by Williams, R. Related Collections Related Article Social Bookmarking                            What's this?