Intramembrane proteolysis by signal peptide peptidases: a comparative discussion of GXGD-type aspartyl proteases

Abstract

Intramembrane-cleaving proteases are required for reverse signaling and membrane protein degradation. A major class of these proteases is represented by the GXGD-type aspartyl proteases. GXGD describes a novel signature sequence that distinguishes these proteases from conventional aspartyl proteases. Members of the family of the GXGD-type aspartyl proteases are the Alzheimer disease-related gamma-secretase, the signal peptide peptidases and their homologs, and the bacterial type IV prepilin peptidases. We will describe the major biochemical and functional properties of the signal peptide peptidases and their relatives. We then compare these properties with those of gamma-secretase and discuss common mechanisms but also point out a number of substantial differences.

FIGURE 1.

A, schematic representation of SPPL2a/b, a member of the SPP/SPPL family, and PS, the catalytic core of theγ-secretase. Note the opposite topology of the active sites (indicated by arrows) of the two proteases and their substrates, APP for PS and TNFα for SPPL2a/b. B, proteolytic processing of APP and TNFα. Shedding releases the extracellular part of APP (APPs) and TNFα (TNFα soluble). In the case of APP, a C-terminal fragment (APP CTF), and in case of TNFα, an N-terminal fragment (TNFα NTF) are produced. These membrane-bound fragments are substrate to intramembrane cleavage by PS or SPPL2a/b, respectively, releasing small peptides to the extracellular space (Aβ and TNFα C-domain, respectively) and to the cytosol (APP intracellular domain (AICD) and TNFα ICD), respectively). TNFα FL, full-length TNFα.

FIGURE 2.

Multiple intramembrane cleavages are mediated byγ-secretase (upper) and SPPL2a/b (lower). The known cleavage sites of γ-secretase in APP (upper) and SPPL2a/b in TNFα (lower) are indicated by arrows. Major cleavage sites in the APP transmembrane domain are indicated by enlarged arrows. Dashed arrows indicate potential direction of the cleavages by the respective intramembrane protease. For APP, two parallel product lines have been suggested, which are initiated by cleavages after amino acid 48 or 49 (5). The initiating cleavage of γ-secretase liberates the APP intracellular domain (AICD) into the cytosol, whereas that of SPPL2a/b liberates the TNFα C-domain into the extracellular space.