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Intra-membrane proteolysis

Cleavage of the transmembrane protein amyloid precursor protein (APP) generates the amyloid ß peptide that accumulates in neuronal plaques in Alzheimer's; a similar cleavage in the Notch receptor releases an intracellular fragment that regulates gene expression during development. Accumulating evidence indicates that the protease responsible (the elusive `-secretase') in both cases is presenilin, together with its cofactors nicastrin, APH-1 and PEN-2. In a Commentary on p. 2839, Weiming Xia and Michael Wolfe discuss recent work suggesting that presenilin is just one of a novel family of transmembrane aspartyl proteases. These include bacterial type 4 perpilin peptidases and signal peptide peptidase (SPP) and share conserved aspartate-containing motifs in one or two of their transmembrane segments. The proteases cleave within the transmembrane domains of their targets and, in the case of presenilin and SPP, prior shedding of the substrate's ectodomain is a prerequisite for cleavage.

Work by Ruth Chiquet-Ehrismann and co-workers also appearing in this issue of JCS hints at another instance of intramembrane proteolysis (see p. 2957). They present evidence that teneurin 2, a neuronal transmembrane protein that is the vertebrate homologue of a fly pair-rule gene product (Ten-m), can release its intracellular domain to function as a transcriptional regulator. The fragment appears to modulate the effect of another pair-rule gene transcription factor, Zic-1, and is released following homophilic interactions between teneurin 2 molecules on neighbouring cells. Whether proteolysis of teneurin 2 is similar to that mediated by presenilin-like proteases remains to be seen; however, similarities between Notch and teneurin 2 such as the presence of furin-cleavage sites in their extracellular domains make this an intriguing possibility.

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Related articles in JCS:

Intramembrane proteolysis by presenilin and presenilin-like proteases

Weiming Xia and Michael S. Wolfe
JCS 2003 116: 2839-2844. [Abstract] [Full Text]  

The intracellular domain of teneurin-2 has a nuclear function and represses zic-1-mediated transcription

Claudia Bagutti, Gaby Forro, Jacqueline Ferralli, Beatrix Rubin, and Ruth Chiquet-Ehrismann
JCS 2003 116: 2957-2966. [Abstract] [Full Text]  

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Related articles in JCS Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Search for Related Content Social Bookmarking                         What's this?