Journal Article

Intramembrane-cleaving aspartic proteases and disease: presenilins, signal peptide peptidase and their homologs

Bruno Martoglio and Todd E. Golde

in Human Molecular Genetics

Volume 12, issue suppl_2, pages R201-R206
Published in print October 2003 | ISSN: 0964-6906
Published online October 2003 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddg303
Intramembrane-cleaving aspartic proteases and disease: presenilins, signal peptide peptidase and their homologs

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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 γ-secretase activity. Because this activity generates the amyloid β peptide (Aβ) 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.

Journal Article.  4900 words.  Illustrated.

Subjects: Genetics and Genomics

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