Signal peptide peptidase

The Signal Peptide Peptidase (SPP) is an intramembrane aspartyl protease with the conserved active site motifs 'YD' and 'GxGD' in in adjacent transmembrane domains (TMDs). Its sequences is highly conserved in different vertebrate species. Its substrates are signal peptides, which upon cleavage by Signal Peptidase span the ER membrane similar to a type II transmembrane protein.

Physiologically SPP processes signal peptides of classical MHC class I preproteins. A nine amino acid-long cleavage fragment is then presented on HLA-E receptors and modulates the activity of natural killer cells.

SPP also plays a pathophysiological role; it cleaves the structural nucleocapsid protein (also known as core protein) of the Hepatitis C virus and thus influences viral reproduction rate.

In mice, a nonamer peptide originating from the SPP protein serves as minor histocompatibility antigen HM13 that plays a role in transplant rejection

The homologous proteases SPPL2A and SPPL2B promote the intramembrane cleavage of TNFα in activated dendritic cells and might play an immunomodulatory role. For SPPL2c and SPPL3 no substrates are known.