Complex Structure and Function of Alzheimer's Enzyme

A new study shows how the gamma-secretase enzyme, which has been implicated in the pathogenic process leading to Alzheimer's disease, functions at the molecular level.

Gamma-secretase, a large, complex enzyme composed of four proteins, slices amyloid precursor protein (APP) into fragments that accumulate as plaques in the brain. The enzyme also interacts with the Notch protein. The core of gamma-secretase is the presenilin protein. Investigators at Washington University (St. Louis, MO, USA; www.wustl.edu) used molecular markers and specific antibodies to show that two molecules of presenilin were located in close proximity to each other. This complicated structure explained why Notch and APP were able to bind freely to the enzyme but competed for access to the cleavage site. These findings were published in the October 28, 2003, online edition of the Proceedings of the National Academy of Sciences.

"The active site is like a mouth: it chews whatever it touches but can only chew one thing at a time,” explained senior author Dr. Raphael Kopan, professor of medicine, molecular biology, and pharmacology at Washington University. "The other site is like a hand: it is used for holding, and does not interfere with the ability of the mouth to chew another object. Maybe one molecule acts as the ‘hand' serving a meal to the ‘mouth,' which is located on another molecule.”



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