Signal peptide peptidase (SPP) catalyzes the liberation of functional signal peptide fragments from the endoplasmic reticulum (ER) membrane. In 21 June Science Andreas Weihofen and colleagues at Swiss Federal Institute of Technology, describe a human SPP and potential eukaryotic homologs which may represent another family of aspartic proteases that promote intramembrane proteolysis, releasing biologically important peptides (Science 2002, 296:2215-2218).

Weihofen et al. identified human SPP as a polytopic membrane protein with sequence motifs characteristic of the presenilin-type aspartic proteases. Based on analysis of glycosylation sites and the prediction of transmembrane regions, they propose a seven-transmembrane topology for SPP with the NH2-terminus in the ER lumen, the COOH-terminus containing the ER retrieval signal in the cytosol and the active-site motifs YD and LGLGD in the center of adjacent transmembrane regions.

"Identification of functional human SPP may allow elucidation of the mechanism of intramembrane proteolysis and address the still-unsolved...