Site-2 protease (S2P) class of zinc metalloproteases (MEROPS family M50) cleaves transmembrane domains of substrate proteins, regulating intramembrane proteolysis (RIP) of diverse signal transduction mechanisms. Members of this family use proteolytic activity within the membrane to transfer information across membranes to integrate gene expression with physiologic stresses occurring in another cellular compartment. The domain core structure appears to contain at least three transmembrane helices with a catalytic zinc atom coordinated by three conserved residues contained within the consensus sequence HExxH, together with a conserved aspartate residue. The S2P/M50 family of RIP proteases is widely distributed; in eukaryotic cells, they regulate such processes as sterol and lipid metabolism, and endoplasmic reticulum (ER) stress responses. In sterol-depleted mammalian cells, a two-step proteolytic process releases the N-terminal domains of sterol regulatory element-binding proteins (SREBPs) from membranes of the ER. These domains translocate into the nucleus, where they activate genes of cholesterol and fatty acid biosynthesis. It is the second proteolytic step that is carried out by the SREBP Site-2 protease (S2P) which is present in this CD superfamily. Prokaryotic S2P/M50 homologs have been shown to regulate stress responses, sporulation, cell division, and cell differentiation. In Escherichia coli, the S2P homolog RseP is involved in the sigmaE pathway of extracytoplasmic stress responses, and in Bacillus subtilis, the S2P homolog SpoIVFB is involved in the pro-sigmaK pathway of spore formation. Some of the subfamilies within this hierarchy contain one or two PDZ domain insertions, with putative regulatory roles, such as the inhibition of substrate cleavage as seen by the RseP PDZ domain.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568077710  44 AFAFLSMYVILILHELGHAFCGYLTGYRlVAFGLGHFILTKKLGRFHLSRTAILknVGAqYIGLKEDESD-------QRI 116
Cdd:cd05709    1 LAFILALLISVTVHELGHALVARRLGVK-VARFSGGFTLNPLKHGDPYGIILIP--LGG-YAKPVGENPRafkkprwQRL 76

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 568077710 117 ILMLSGGLM-VHLSLILLAIVFGFLTRS------------WYFAGTWIFLNLSFFLNNILPVGITDGAKIWELL 177
Cdd:cd05709   77 LVALAGPLAnLLLALLLLLLLLLLGGLPpapvgqaassglANLLAFLALINLNLAVFNLLPIPPLDGGRILRAL 150

Site-2 protease (S2P) class of zinc metalloproteases (MEROPS family M50) cleaves transmembrane domains of substrate proteins, regulating intramembrane proteolysis (RIP) of diverse signal transduction mechanisms. Members of this family use proteolytic activity within the membrane to transfer information across membranes to integrate gene expression with physiologic stresses occurring in another cellular compartment. The domain core structure appears to contain at least three transmembrane helices with a catalytic zinc atom coordinated by three conserved residues contained within the consensus sequence HExxH, together with a conserved aspartate residue. The S2P/M50 family of RIP proteases is widely distributed; in eukaryotic cells, they regulate such processes as sterol and lipid metabolism, and endoplasmic reticulum (ER) stress responses. In sterol-depleted mammalian cells, a two-step proteolytic process releases the N-terminal domains of sterol regulatory element-binding proteins (SREBPs) from membranes of the ER. These domains translocate into the nucleus, where they activate genes of cholesterol and fatty acid biosynthesis. It is the second proteolytic step that is carried out by the SREBP Site-2 protease (S2P) which is present in this CD superfamily. Prokaryotic S2P/M50 homologs have been shown to regulate stress responses, sporulation, cell division, and cell differentiation. In Escherichia coli, the S2P homolog RseP is involved in the sigmaE pathway of extracytoplasmic stress responses, and in Bacillus subtilis, the S2P homolog SpoIVFB is involved in the pro-sigmaK pathway of spore formation. Some of the subfamilies within this hierarchy contain one or two PDZ domain insertions, with putative regulatory roles, such as the inhibition of substrate cleavage as seen by the RseP PDZ domain.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568077710  44 AFAFLSMYVILILHELGHAFCGYLTGYRlVAFGLGHFILTKKLGRFHLSRTAILknVGAqYIGLKEDESD-------QRI 116
Cdd:cd05709    1 LAFILALLISVTVHELGHALVARRLGVK-VARFSGGFTLNPLKHGDPYGIILIP--LGG-YAKPVGENPRafkkprwQRL 76

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 568077710 117 ILMLSGGLM-VHLSLILLAIVFGFLTRS------------WYFAGTWIFLNLSFFLNNILPVGITDGAKIWELL 177
Cdd:cd05709   77 LVALAGPLAnLLLALLLLLLLLLLGGLPpapvgqaassglANLLAFLALINLNLAVFNLLPIPPLDGGRILRAL 150

Site-2 protease (S2P) class of zinc metalloproteases (MEROPS family M50) cleaves transmembrane domains of substrate proteins, regulating intramembrane proteolysis (RIP) of diverse signal transduction mechanisms. Members of this family use proteolytic activity within the membrane to transfer information across membranes to integrate gene expression with physiologic stresses occurring in another cellular compartment. The domain core structure appears to contain at least three transmembrane helices with a catalytic zinc atom coordinated by three conserved residues contained within the consensus sequence HExxH, together with a conserved aspartate residue. The S2P/M50 family of RIP proteases is widely distributed; in eukaryotic cells, they regulate such processes as sterol and lipid metabolism, and endoplasmic reticulum (ER) stress responses. In sterol-depleted mammalian cells, a two-step proteolytic process releases the N-terminal domains of sterol regulatory element-binding proteins (SREBPs) from membranes of the ER. These domains translocate into the nucleus, where they activate genes of cholesterol and fatty acid biosynthesis. It is the second proteolytic step that is carried out by the SREBP Site-2 protease (S2P) which is present in this CD superfamily. Prokaryotic S2P/M50 homologs have been shown to regulate stress responses, sporulation, cell division, and cell differentiation. In Escherichia coli, the S2P homolog RseP is involved in the sigmaE pathway of extracytoplasmic stress responses, and in Bacillus subtilis, the S2P homolog SpoIVFB is involved in the pro-sigmaK pathway of spore formation. Some of the subfamilies within this hierarchy contain one or two PDZ domain insertions, with putative regulatory roles, such as the inhibition of substrate cleavage as seen by the RseP PDZ domain.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568077710  44 AFAFLSMYVILILHELGHAFCGYLTGYRlVAFGLGHFILTKKLGRFHLSRTAILknVGAqYIGLKEDESD-------QRI 116
Cdd:cd05709    1 LAFILALLISVTVHELGHALVARRLGVK-VARFSGGFTLNPLKHGDPYGIILIP--LGG-YAKPVGENPRafkkprwQRL 76

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 568077710 117 ILMLSGGLM-VHLSLILLAIVFGFLTRS------------WYFAGTWIFLNLSFFLNNILPVGITDGAKIWELL 177
Cdd:cd05709   77 LVALAGPLAnLLLALLLLLLLLLLGGLPpapvgqaassglANLLAFLALINLNLAVFNLLPIPPLDGGRILRAL 150

RseP-like Site-2 proteases (S2P), zinc metalloproteases (MEROPS family M50A), cleave transmembrane domains of substrate proteins, regulating intramembrane proteolysis (RIP) of diverse signal transduction mechanisms. In Escherichia coli, the S2P homolog RseP is involved in the sigmaE pathway of extracytoplasmic stress responses. Also included in this group are such homologs as Bacillus subtilis YluC, Mycobacterium tuberculosis Rv2869c S2P, and Bordetella bronchiseptica HurP. Rv2869c S2P appears to have a role in the regulation of prokaryotic lipid biosynthesis and membrane composition and YluC of Bacillus has a role in transducing membrane stress. This group includes bacterial and eukaryotic S2P/M50s homologs with either one or two PDZ domains present. PDZ domains are believed to have a regulatory role. The RseP PDZ domain is required for the inhibitory reaction that prevents cleavage of its substrate, RseA.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568077710  45 FAFLSMYVILILHELGHAFCGYLTGYRLVAF--GLGHFILTKKLG--RFHLSrtAILknVGAqYIGLKEDESD------- 113
Cdd:cd06163    3 AFILVLGILIFVHELGHFLVAKLFGVKVEEFsiGFGPKLFSFKKGetEYSIS--AIP--LGG-YVKMLGEDPEeeadped 77

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 568077710 114 -----------QRIILMLSGGLM-VHLSLILLAIVFGFLTrswyfagtwiFLNLSFFLNNILPVGITDGAKIWELL 177
Cdd:cd06163   78 dprsfnskpvwQRILIVFAGPLAnFLLAIVLFAVLLSFLA----------LLSINLGILNLLPIPALDGGHLLFLL 143