Site-2 protease regulated intramembrane proteolysis: sequence homologs suggest an ancient signaling cascade

Protein Sci. 2006 Jan;15(1):84-93. doi: 10.1110/ps.051766506. Epub 2005 Dec 1.


Site-2 proteases (S2Ps) form a large family of membrane-embedded metalloproteases that participate in cellular signaling pathways through sequential cleavage of membrane-tethered substrates. Using sequence similarity searches, we extend the S2P family to include remote homologs that help define a conserved structural core consisting of three predicted transmembrane helices with traditional metalloprotease functional motifs and a previously unrecognized motif (GxxxN/S/G). S2P relatives were identified in genomes from Bacteria, Archaea, and Eukaryota including protists, plants, fungi, and animals. The diverse S2P homologs divide into several groups that differ in various inserted domains and transmembrane helices. Mammalian S2P proteases belong to the major ubiquitous group and contain a PDZ domain. Sequence and structural analysis of the PDZ domain support its mediating the sequential cleavage of membrane-tethered substrates. Finally, conserved genomic neighborhoods of S2P homologs allow functional predictions for PDZ-containing transmembrane proteases in extra-cytoplasmic stress response and lipid metabolism.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Archaeal Proteins / chemistry
  • Archaeal Proteins / genetics
  • Archaeal Proteins / physiology
  • Bacterial Proteins / chemistry
  • Bacterial Proteins / genetics
  • Bacterial Proteins / physiology
  • Cell Membrane / enzymology*
  • Cell Membrane / genetics
  • Conserved Sequence
  • Endopeptidases / chemistry*
  • Endopeptidases / genetics
  • Endopeptidases / physiology*
  • Evolution, Molecular*
  • Humans
  • Hydrolysis
  • Membrane Proteins
  • Metalloendopeptidases
  • Molecular Sequence Data
  • Phylogeny
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Sequence Homology, Amino Acid*
  • Signal Transduction / genetics
  • Signal Transduction / physiology*


  • Archaeal Proteins
  • Bacterial Proteins
  • Membrane Proteins
  • spoIV protein, Bacillus megaterium
  • Endopeptidases
  • Metalloendopeptidases
  • MBTPS2 protein, human
  • SREBP site 2 protease