Signal peptide peptidases: a family of intramembrane-cleaving proteases that cleave type 2 transmembrane proteins

Abstract

Five genes encode the five human signal peptide peptidases (SPPs), which are intramembrane-cleaving aspartyl proteases (aspartyl I-CLiPs). SPPs have been conserved through evolution with family members found in higher eukaryotes, fungi, protozoa, arachea, and plants. SPPs are related to the presenilin family of aspartyl I-CLiPs but differ in several key aspects. Presenilins (PSENs) and SPPs both cleave the transmembrane region of membrane proteins; however, PSENs cleave type 1 membrane proteins whereas SPPs cleave type 2 membrane proteins. Though the overall homology between SPPs and PSENs is minimal, they are 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 COOH-termini. They differ in that the active site YD and GxGD containing transmembrane domains of SPPs are inverted relative to PSENs, thus, orienting the active site in a consistent topology relative to the substrate. At least two of the human SPPs (SPP and SPPL3) appear to function without additional cofactors, but PSENs function as a protease, called gamma-secretase, only when complexed with Nicastrin, APH-1 and Pen-2. The biological roles of SPP are largely unknown, and only a few endogenous substrates for SPPs have been identified. Nevertheless there is emerging evidence that SPP family members are highly druggable and may regulate both essential physiologic and pathophysiologic processes. Further study of the SPP family is needed in order to understand their biological roles and their potential as therapeutic targets.

Fig. 1

A phylogenetic tree of the various SPPs that have been studied to date is shown. This tree was created using the multiple alignment sequence program found at http://3w.molgen.mpg.de/. Protein sequences used to generate the alignment and the phylogenetic tree are shown in parenthesis. Note that such an alignment suggests that one of the Drosophila Melanogaster SPPs (NP 651437) should probably be renamed SPPL3. The phylogenetic tree demonstrates that the SPP and SPPL3 orthologs are more closely related then the SPPL2 family members.

Fig. 2

A schematic of SPP and PSEN show that they are multipass membrane protein that contains two catalytic aspartate residues indicated by the stars. These aspartates are present in opposing and adjacent transmembrane domains. A third conserved motif in is the PAL motif near the carboxyl-terminus (red triangle). As depicted, SPP and its homologs cleave type 2 membrane proteins. Althougha7TMD model is shown, other models suggest additional TMDs. For either model the exact topology of SPP has not been experimentally validated. PSEN exhibit an inverted topology relative to SPP. The schematic shows the 9 TMD topology model for PSEN which has been extensively validated using genetic and biochemical methods [59].