title: A family of membrane-embedded metalloproteases involved in regulated proteolysis of membrane-associated transcription factors.
abstract: We present evidence that the sporulation protein SpoIVFB of Bacillus subtilis is a member of a newly recognized family of metalloproteases that have catalytic centers adjacent to or within the membrane. SpoIVFB is required for converting the membrane-associated precursor protein, pro-sigma(K), to the mature and active transcription factor sigma(K) by proteolytic removal of an N-terminal extension of 20 amino acids. SpoIVFB and other family members share the conserved sequence HEXXH, a hallmark of metalloproteases, as well as a second conserved motif NPDG, which is unique to the family. Both motifs, which are expected to form the catalytic center of the protease, overlap hydrophobic segments that are predicted to be separate transmembrane domains. The only other characterized member of this family of membrane-embedded metalloproteases is the mammalian Site-2 protease (S2P), which is required for the intramembrane cleavage of the eukaryotic transcription factor sterol regulatory element binding protein (SREBP). We report that amino acid substitutions in the two conserved motifs of SpoIVFB impair pro-sigma(K) processing and sigma(K)-directed gene expression during sporulation. These results and those from a similar analysis of S2P support the interpretation that both proteins are founding members of a family of metalloproteases involved in the activation of membrane-associated transcription factors. Thus, the pathways that govern the activation of the prokaryotic transcription factor pro-sigma(K) and the mammalian transcription factor SREBP not only are analogous but also use processing enzymes with strikingly homologous features.
authors.affiliation: Department of Molecular Biology, Harvard University, 16 Divinity Avenue, Cambridge, MA 02138, USA.
authors.forename: D Z
authors.initials: DZ
authors.lastname: Rudner
authors.forename: P
authors.initials: P
authors.lastname: Fawcett
authors.forename: R
authors.initials: R
authors.lastname: Losick
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001412:Bacillus subtilis / Q000502:physiology; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D020134:Catalytic Domain; D017124:Conserved Sequence; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D005810:Multigene Family; D009154:Mutation; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D020539:Sequence Analysis, Protein; D017386:Sequence Homology, Amino Acid; D012808:Sigma Factor / Q000378:metabolism*; D013171:Spores, Bacterial; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D008565:Membrane Proteins; D011498:Protein Precursors; D012808:Sigma Factor; D014157:Transcription Factors; C112176:pro-sigmaK protein, Bacillus subtilis; C088067:spoIV protein, Bacillus megaterium; D008666:Metalloendopeptidases