Human Molecular Genetics Advance Access originally published online on September 9, 2003
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Human Molecular Genetics, 2003, Vol. 12, Review Issue 2 R201-R206
DOI: 10.1093/hmg/ddg303
© 2003 Oxford University Press
Intramembrane-cleaving aspartic proteases and disease: presenilins, signal peptide peptidase and their homologs
1Institute of Biochemistry, Swiss Federal Institute of Technology (ETH), ETH-Hoenggerberg, 8093 Zurich, Switzerland and 2Department of Neuroscience, Mayo Graduate School, Mayo Clinic Jacksonville, Jacksonville, FL 32224, USA
Received June 30, 2003; Accepted August 14, 2003
Recent studies demonstrate that presenilins (PSs) and signal peptide peptidase (SPP) are members of a novel protease family of integral membrane proteins that may utilize a catalytic mechanism similar to classic aspartic proteases such as pepsin, renin and cathepsin D. The defining features of the PSs and SPP are their ability to cleave substrate polypeptides within a transmembrane region, the presence of two active site aspartate residues in adjacent membrane-spanning regions and a conserved PAL motif near their COOH-terminus. PSs appear to be the catalytic subunit of multiprotein complexes that possess 
-secretase activity. Because this activity generates the amyloid ß peptide (Aß) deposited in the brain of patients with Alzheimer's disease (AD), PSs are considered therapeutic targets in AD. In contrast to PSs that are not active unless part of a larger complex, SPP does not appear to require protein co-factors. Because of its requirement for hepatitis C virus maturation and a possible immune modulatory role, SPP is also considered a potential therapeutic target. Four additional PS/SPP homologs have been identified in humans; yet, their functions have not been elucidated. Herein, we will review the recent advances in our understanding of the PS/SPP family of proteases as well as discuss aspects of intramembrane cleavage that are not well understood.
* Correspondence can be addressed to Bruno Martoglio, Tel +41 16326347; Fax: +41 16321269; Email: bruno.martoglio{at}bc.biol.ethz.ch or Todd E. Golde, Tel: +1 9049532538; Fax: +1 9049537370; Email: tgolde{at}mayo.edu
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