Signal Peptide Peptidase-Type Proteases: Versatile Regulators with Functions Ranging from Limited Proteolysis to Protein Degradation

J Mol Biol. 2020 Aug 21;432(18):5063-5078. doi: 10.1016/j.jmb.2020.05.014. Epub 2020 May 26.


Intramembrane proteases catalyze the unusual cleavage of peptide bonds in the plane of biological membranes. They are categorized according to their active site. The GxGD aspartyl proteases comprise presenilin, the signal peptide peptidase (SPP), and SPP-like (SPPL) proteases. Here we focus on the functionally related SPP and SPPL proteases, and review the current understanding of their substrate specificity and summarize known physiological functions in mammalian cells. We discuss how on the one hand regulated intramembrane proteolysis generates signaling molecules, and on the other hand how processes such as endoplasmic reticulum-associated degradation controls the quantity and activity of central regulators. While the enzymatic core of GxGD intramembrane proteases is conserved, association with regulatory factors and substrate adaptors may have tailored enzymes for various specific functions.

Keywords: intramembrane proteolysis; limited proteolysis; presenilin fold; protein degradation; signaling.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Aspartic Acid Endopeptidases / chemistry*
  • Aspartic Acid Endopeptidases / metabolism*
  • Catalytic Domain
  • Cell Membrane / enzymology*
  • Endoplasmic Reticulum / metabolism
  • Humans
  • Phylogeny
  • Protein Transport
  • Proteolysis


  • Aspartic Acid Endopeptidases
  • signal peptide peptidase