Zn-dependent protease (includes sporulation protein SpoIVFB) [Posttranslational modification, protein turnover, chaperones];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 818807185  11 LIFYFLILVFSVIIHEVAHGYVAKIQGDDTAetlgRLTLNPLAhidpfgsvilpglliflslithssmflFGWAKpVPFN 90
Cdd:COG1994   11 ILIFALALFLSVLLHELAHALVARRLGDPTA----KITLNPLK---------------------------GGWAK-INRN 58

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 818807185  91 PLKlkdiRWGPVWVACAGAGANFLIAILFALLMRFGAIGFGPAAVIMFSTIVLTNLMLAVFNLMPIPPLDGSKILAGIVG 170
Cdd:COG1994   59 FRN----PRDEALVALAGPLANLLLALLFALLLRLLPALGLGPLALLLGYLALINLVLAVFNLLPIPPLDGGRILRALLP 134

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|.
gi 818807185 171 DRW----TTIERFLSTNSLLIFALFLMFGSYFIMPIVSFLY 207
Cdd:COG1994  135 RRTarraTRLEPYGFLILLLLIFLGLLLGNIWLSPLLNLLI 175

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 818807185  12 IFYFLILVFSVIIHEVAHGYVAKIQGDDTAETLGRLTLNPLAHIDPFGSVILPglliflslithssmfLFGWAKPVPFNP 91
Cdd:cd05709    1 LAFILALLISVTVHELGHALVARRLGVKVARFSGGFTLNPLKHGDPYGIILIP---------------LGGYAKPVGENP 65

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 818807185  92 LKLKDIRWGPVWVACAGAGANFLIAILFALLMRFGAIGFGPA--------AVIMFSTIVLTNLMLAVFNLMPIPPLDGSK 163
Cdd:cd05709   66 RAFKKPRWQRLLVALAGPLANLLLALLLLLLLLLLGGLPPAPvgqaassgLANLLAFLALINLNLAVFNLLPIPPLDGGR 145

                        170       180       190
                 ....*....|....*....|....*....|....*
gi 818807185 164 ILAGIVGDRWTTIERFLSTNSLLIFALFLMFGSYF 198
Cdd:cd05709  146 ILRALLEAIRGRVEERLEAYGFAILLGLLLLLLLN 180

SpoIVFB Site-2 protease (S2P), a zinc metalloprotease (MEROPS family M50B), regulates intramembrane proteolysis (RIP), and is involved in the pro-sigmaK pathway of bacterial spore formation. In this subgroup, SpoIVFB (sporulation protein, stage IV cell wall formation, F locus, promoter-distal B) contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domain. SpoIVFB is one of 4 proteins involved in endospore formation; the others are SpoIVFA (sporulation protein, stage IV cell wall formation, F locus, promoter-proximal A), BofA (bypass-of-forespore A), and SpoIVB (sporulation protein, stage IV cell wall formation, B locus). SpoIVFB is negatively regulated by SpoIVFA and BofA and activated by SpoIVB. It is thought that SpoIVFB, SpoIVFA, and BofA are located in the mother-cell membrane that surrounds the forespore and that SpoIVB is secreted from the forespore into the space between the two where it activates SpoIVFB. It has been proposed that the CBS domain may play a regulatory role, although its exact function is unknown.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 818807185  12 IFYFLILVFSVIIHEVAHGYVAKIQGDDTAetlgRLTLNPlahidpFGSVilpglliflslithSSMflfgwaKPVPFNP 91
Cdd:cd06164   46 LAAALLLFASVLLHELGHSLVARRYGIPVR----SITLFL------FGGV--------------ARL------EREPETP 95

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 818807185  92 lklkdirWGPVWVACAGAGANFLIAILFALLMRFGAIGFGPAAVIMFSTIVLTNLMLAVFNLMPIPPLDGSKILAGIVgd 171
Cdd:cd06164   96 -------GQEFVIAIAGPLVSLVLALLFLLLSLALPGSGAGPLGVLLGYLALINLLLAVFNLLPAFPLDGGRVLRALL-- 166

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|....*
gi 818807185 172 rWTTIERFL-----STNSLLIFALFLMFGSyFIMPIVSFLYGLLT 211
Cdd:cd06164  167 -WRRTGDYLkatriAAWVGRGFAVLLIILG-LLSLFLNLLGGLWL 209

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 818807185  99 WGPVWVACAGAGANFLIAI-LFALLMRFGAigfgpaavimfstivLTNLMLAVFNLMPIPPLDGSKIL 165
Cdd:cd06163   88 WQRILIVFAGPLANFLLAIvLFAVLLSFLA---------------LLSINLGILNLLPIPALDGGHLL 140

Uncharacterized homologs of Site-2 protease (S2P), zinc metalloproteases (MEROPS family M50) which cleave transmembrane domains of substrate proteins, regulating intramembrane proteolysis (RIP) of diverse signal transduction mechanisms. Members of the S2P/M50 family of RIP proteases use proteolytic activity within the membrane to transfer information across membranes to integrate gene expression with physiologic stresses occurring in another cellular compartment. In eukaryotic cells they regulate such processes as sterol and lipid metabolism, and endoplasmic reticulum stress responses. In prokaryotes they regulate such processes as sporulation, cell division, stress response, and cell differentiation. This group includes bacterial, eukaryotic, and Archaeal S2P/M50s homologs with additional putative N- and C-terminal transmembrane spanning regions, relative to the core protein, and no PDZ domains.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 818807185 125 FGAIGFGPAAVIMFSTIVLTNLMLAVFNLMPIPPLDGSKILAGIVGDRWTTIERFLSTNSLLIFALFLMFGSYFIMPIVS 204
Cdd:cd06160  102 AGLLLALPVLIIGLAVAGWVGLLVTALNLLPVGQLDGGHIVRALFGRRVAALIGIGLLVALGLLALYLSFSIWLLWALLL 181

                 ..
gi 818807185 205 FL 206
Cdd:cd06160  182 LI 183