title: Site-2 protease regulated intramembrane proteolysis: sequence homologs suggest an ancient signaling cascade.
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 extra-cytoplasmic stress response and lipid metabolism.
authors.affiliation: Howard Hughes Medical Institute and Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9050, USA. lkinch@chop.swmed.edu
authors.forename: Lisa N
authors.initials: LN
authors.lastname: Kinch
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Ginalski
authors.forename: Nick V
authors.initials: NV
authors.lastname: Grishin
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019843:Archaeal Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D002462:Cell Membrane / Q000201:enzymology* / Q000235:genetics; D017124:Conserved Sequence; D010450:Endopeptidases / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D019143:Evolution, Molecular; D006801:Humans; D006868:Hydrolysis; D008565:Membrane Proteins; D008666:Metalloendopeptidases; D008969:Molecular Sequence Data; D010802:Phylogeny; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*
chemical_list: D019843:Archaeal Proteins; D001426:Bacterial Proteins; D008565:Membrane Proteins; C088067:spoIV protein, Bacillus megaterium; D010450:Endopeptidases; D008666:Metalloendopeptidases; C120654:MBTPS2 protein, human; C112686:SREBP site 2 protease