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1 Howard Hughes Medical Institute and Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9050, USA
2 Interdisciplinary Centre for Mathematical and Computational Modelling, Warsaw University, 02-106 Warsaw, Poland
(RECEIVED August 10, 2005; FINAL REVISION September 29, 2005; ACCEPTED September 29, 2005)
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 metal-loprotease 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.
Keywords: site-2 protease; regulated intramembrane proteolysis; phylogenetic analysis; domain organization; motif recognition; functional prediction
Abbreviations: Rip, regulated intramembrane proteolysis • TMH, transmembrane-spanning helix • S2P, site 2 protease • ER, endoplasmic reticulum • SREBP, sterol regulatory element-binding protein
Article published online ahead of print. Article and publication date are at http://www.proteinscience.org/cgi/doi/10.1110/ps.051766506.
Reprint requests to: Lisa N. Kinch, Howard Hughes Medical Institute and Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9050, USA; e-mail: lkinch{at}chop.swmed.edu; fax: (214) 645-5948.
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