PMID: 15385547

 

    Legend: Sugar

Title : Consensus analysis of signal peptide peptidase and homologous human aspartic proteases reveals opposite topology of catalytic domains compared with presenilins

Abstract :
  1. The human genome encodes seven intramembrane-cleaving GXGD aspartic proteases
  2. These are the two presenilins that activate signaling molecules and are implicated in Alzheimer's disease, signal peptide peptidase ( SPP ), required for immune surveillance, and four SPP-like candidate proteases (SPPLs), of unknown function
  3. Here we describe a comparative analysis of the topologies of SPP and its human homologues, SPPL2a, -2b, -2c, and -3
  4. We demonstrate that their N-terminal extensions are located in the extracellular space and, except for SPPL3 , are modified with N-glycans
  5. Whereas SPPL2a , -2b, and -2c contain a signal sequence , SPP and SPPL3 contain a type I signal anchor sequence for initiation of protein translocation and membrane insertion
  6. The hydrophilic loops joining the transmembrane regions , which contain the catalytic residues , are facing the exoplasm
  7. The C termini of all these proteins are exposed toward the cytosol
  8. Taken together, our study demonstrates that SPP and its homologues are all of the same principal structure with a catalytic domain embedded in the membrane in opposite orientation to that of presenilins
  9. Other than presenilins, SPPL2a, -2b, -2c, and -3 are therefore predicted to cleave type II-oriented substrate peptides like the prototypic protease SPP