title: Molecular insights into mechanisms of intramembrane proteolysis through signal peptide peptidase (SPP).
abstract: The processing of membrane-anchored signalling molecules and transcription factors by RIP (regulated intramembrane proteolysis) is a major signalling paradigm in eukaryotic cells. Intramembrane cleaving proteases liberate fragments from membrane-bound precursor proteins which typically fulfil functions such as cell signalling and regulation, immunosurveillance and intercellular communication. Furthermore, they are thought to be involved in the development and propagation of several diseases, such as Alzheimer's disease and hepatitis C virus infection. In this issue of the Biochemical Journal, Schrul and colleagues investigate the interaction of the endoplasmic reticulum-resident intramembrane cleaving SPP (signal peptide peptidase) with different type II oriented transmembrane proteins. A combination of co-immunoprecipitation experiments using wild-type and a dominant-negative SPP with electrophoretic protein separations under native conditions revealed selectivity of the interaction. Depending on the interacting protein, SPP formed complexes of different sizes. SPP could build tight interactions not only with signal peptides, but also with pre- and mis-folded proteins. Whereas signal peptides are direct substrates for SPP proteolysis, the study suggests that SPP may be involved in the controlled sequestration of possibly toxic membrane protein species in a proteolysis-independent manner. These large oligomeric membrane protein aggregates may then be degraded by the proteasome or autophagy.
authors.affiliation: Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Schröder
authors.forename: Paul
authors.initials: P
authors.lastname: Saftig
mesh_terms: D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D011485:Protein Binding
chemical_list: D008565:Membrane Proteins; D016282:Aspartic Acid Endopeptidases; C460085:signal peptide peptidase