SIGNAL PEPTIDE PEPTIDASES

Signal peptide peptidases (SPPs) are the most recently identified members of a protease family of integral membrane proteins that includes the intensively studied presenilin 1 (PS1) and presenilin (PS2) proteins. There are 5 human genes encoding SPPs which can be divided into two branches based on homology and initial functional studies. One branch, which is the focus of this chapter, consists of the SPP and SPPL3 proteins. The second branch will be the focus of a subsequent chapter, and consists of the three SPPL2 proteins (SPPL2a, b, and c). The SPP proteins are conserved through evolution with family members found in fungi, archaea and plants. Presenilins (PSs) and SPPs cleave substrate polypeptides within a transmembrane region, but differ in that PSs cleave type 1 membrane proteins whereas SPPs cleave type 2 membrane proteins. SPPs and PSs have low overall sequence homology, yet exhibit considerable structural similarity as well as strict conservation of several small motifs. They are both multipass membrane proteins that contain two conserved active site motifs YD and GxGD in adjacent membrane-spanning domains and a conserved PAL motif of unknown function near their C-termini. They differ in that the active site topology of SPPs is inverted relative to PSs. Moreover, SPP and SPPL3 appear to function as proteases without the need for additional cofactors. In contrast, PSs function as the UPgamma-secretase protease only when complexed with three accessory proteins. Although the biological roles of PSs are reasonably well understood, the biological roles of SPP are largely unknown, and only a few endogenous substrates for SPP have been identified. SPP and possibly SPPL3 appear to cleave a number of endogenous type 2 signal peptides and these genes are essential genes in the development of several model organisms. In addition, in many human parasites, there is only a single SPP gene that is most closely related to the human SPP. Thus, SPPs may be novel antiviral drug targets in humans and represent a novel drug target for major human pathogens such as malaria