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

Lisa N. Kinch, Krzysztof Ginalski, Nick V. Grishin

Research output: Contribution to journalArticle

61 Citations (Scopus)

Abstract

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 extracytoplasmic stress response and lipid metabolism. Published by Cold Spring Harbor Laboratory Press.

Original languageEnglish (US)
Pages (from-to)84-93
Number of pages10
JournalProtein Science
Volume15
Issue number1
DOIs
StatePublished - Jan 2006

Fingerprint

Proteolysis
Sequence Homology
PDZ Domains
Peptide Hydrolases
Metalloproteases
Membranes
Cell signaling
Archaea
Substrates
Ports and harbors
Eukaryota
Fungi
Lipid Metabolism
Structural analysis
Sequence Analysis
Bacteria
Animals
Genes
Genome

Keywords

  • Domain organization
  • Functional prediction
  • Motif recognition
  • Phylogenetic analysis
  • Regulated intramembrane proteolysis
  • Site-2 protease

ASJC Scopus subject areas

  • Biochemistry

Cite this

Site-2 protease regulated intramembrane proteolysis : Sequence homologs suggest an ancient signaling cascade. / Kinch, Lisa N.; Ginalski, Krzysztof; Grishin, Nick V.

In: Protein Science, Vol. 15, No. 1, 01.2006, p. 84-93.

Research output: Contribution to journalArticle

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