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 1573864603  98 LWIVVLIGAWYLGLLALERRGILDRWNATraLGIILMLRTNRGKRVLELVSQPRRFWRAYGELSIWLCFAVMAGVLLLLF 177
Cdd:cd06159     1 YLALILFLIYWILISILRKRGILEYNIST--YGPFLMLRTKKGRGFIDKLARPKRFWRAFGNIGIPIAFVGMIFMLLLIL 78

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1573864603 178 LSALAITMDPGQEVLPARDLLLIPGVTSFVPFWWPVAALIIALIIHEYSHGIQARAHGMQVRSFGLLLAGpLPVGAFAEP 257
Cdd:cd06159    79 LSAIIILSGPPAPLNAPRNVLVIPGVNIFIPLPYGIIALVVGVVVHELSHGILARVEGIKVKSGGLLLLI-IPPGAFVEP 157

                         170       180       190       200
                  ....*....|....*....|....*....|....*....|..
gi 1573864603 258 EYEEMIRAPRRERMRLYAAGPSINLLACWIVLILLSATATGF 299
Cdd:cd06159   158 DEEELNKADRRIRLRIFAAGVTANFVVALIAFALFFLYWIFW 199

Uncharacterized Archaeal 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 appears to be limited to Archaeal S2P/M50s homologs with additional putative N-terminal transmembrane spanning regions, relative to the core protein, and either one or two PDZ domains present.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1573864603  98 LWIVVLIGAWYLGLLALERRGILDRWNATraLGIILMLRTNRGKRVLELVSQPRRFWRAYGELSIWLCFAVMAGVLLLLF 177
Cdd:cd06159     1 YLALILFLIYWILISILRKRGILEYNIST--YGPFLMLRTKKGRGFIDKLARPKRFWRAFGNIGIPIAFVGMIFMLLLIL 78

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1573864603 178 LSALAITMDPGQEVLPARDLLLIPGVTSFVPFWWPVAALIIALIIHEYSHGIQARAHGMQVRSFGLLLAGpLPVGAFAEP 257
Cdd:cd06159    79 LSAIIILSGPPAPLNAPRNVLVIPGVNIFIPLPYGIIALVVGVVVHELSHGILARVEGIKVKSGGLLLLI-IPPGAFVEP 157

                         170       180       190       200
                  ....*....|....*....|....*....|....*....|..
gi 1573864603 258 EYEEMIRAPRRERMRLYAAGPSINLLACWIVLILLSATATGF 299
Cdd:cd06159   158 DEEELNKADRRIRLRIFAAGVTANFVVALIAFALFFLYWIFW 199

Membrane-associated protease RseP, regulator of RpoE activity [Posttranslational modification, protein turnover, chaperones, Transcription];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1573864603 209 FWWPVAALIIAL----IIHEYSHGIQARAHGMQVRSFGL-----LLA----------GPLPVGAF-------------AE 256
Cdd:COG0750     3 FLLTILAFILVLgvlvFVHELGHFLVARLFGVKVEEFSIgfgpkLFSkkrgeteygiRAIPLGGYvkmagmdpesevaPE 82

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1573864603 257 PEYEEMIRAPRRERMRLYAAGPSINLLACWIVLILLsATATGFAATNDGVhaVG-IIEDTGAEDAGLKPYETITQINDVP 335
Cdd:COG0750    83 DDPRAFNSKPVWQRLIIVLAGPLANFLLAIVLFAVL-FMTVGVPVLTPPV--VGeVVPGSPAAKAGLQPGDRIVAINGQP 159

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1573864603 336 VIDYSSFTEVMSDfEAGDSATMTVltppsqgeveerlievvftdswdyhmnecrERENcdeaALEELLAKLKIKKGD--A 413
Cdd:COG0750   160 VTSWDDLVDIIRA-SPGKPLTLTV------------------------------ERDG----EELTLTVTPRLVEEDgvG 204

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1573864603 414 FLGVS-GLQSSTAAVDNWGYFfnddYDASEKVVGTIFAPLAMLGVPIALDGHTMNLeqramltAGDGAIASTLGTEGMLA 492
Cdd:COG0750   205 RIGVSpSGEVVTVRYGPLEAL----GAGVKETWDMIVLTLKGLGKLITGKVSAKNL-------SGPIGIAGIAGEAASSG 273

                         330       340       350
                  ....*....|....*....|....*....|..
gi 1573864603 493 AFDFLFWLAWINFLLGFANLIPMVPFDGGHLV 524
Cdd:COG0750   274 LASFLSFLALLSINLGVLNLLPIPALDGGHLL 305

periplasmic serine protease, Do/DeqQ family; This family consists of a set proteins various designated DegP, heat shock protein HtrA, and protease DO. The ortholog in Pseudomonas aeruginosa is designated MucD and is found in an operon that controls mucoid phenotype. This family also includes the DegQ (HhoA) paralog in E. coli which can rescue a DegP mutant, but not the smaller DegS paralog, which cannot. Members of this family are located in the periplasm and have separable functions as both protease and chaperone. Members have a trypsin domain and two copies of a PDZ domain. This protein protects bacteria from thermal and other stresses and may be important for the survival of bacterial pathogens.// The chaperone function is dominant at low temperatures, whereas the proteolytic activity is turned on at elevated temperatures. [Protein fate, Protein folding and stabilization, Protein fate, Degradation of proteins, peptides, and glycopeptides]

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1573864603 305 GVHAVGIIEDTGAEDAGLKPYETITQINDVPVIDYSSFTEVMSDFEAGDSATMTVL 360
Cdd:TIGR02037 258 GALVAQVLPGSPAEKAGLKAGDVITSVNGKPISSFADLRRAIGTLKPGKKVTLGIL 313

Uncharacterized Archaeal 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 appears to be limited to Archaeal S2P/M50s homologs with additional putative N-terminal transmembrane spanning regions, relative to the core protein, and either one or two PDZ domains present.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1573864603  98 LWIVVLIGAWYLGLLALERRGILDRWNATraLGIILMLRTNRGKRVLELVSQPRRFWRAYGELSIWLCFAVMAGVLLLLF 177
Cdd:cd06159     1 YLALILFLIYWILISILRKRGILEYNIST--YGPFLMLRTKKGRGFIDKLARPKRFWRAFGNIGIPIAFVGMIFMLLLIL 78

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1573864603 178 LSALAITMDPGQEVLPARDLLLIPGVTSFVPFWWPVAALIIALIIHEYSHGIQARAHGMQVRSFGLLLAGpLPVGAFAEP 257
Cdd:cd06159    79 LSAIIILSGPPAPLNAPRNVLVIPGVNIFIPLPYGIIALVVGVVVHELSHGILARVEGIKVKSGGLLLLI-IPPGAFVEP 157

                         170       180       190       200
                  ....*....|....*....|....*....|....*....|..
gi 1573864603 258 EYEEMIRAPRRERMRLYAAGPSINLLACWIVLILLSATATGF 299
Cdd:cd06159   158 DEEELNKADRRIRLRIFAAGVTANFVVALIAFALFFLYWIFW 199

Membrane-associated protease RseP, regulator of RpoE activity [Posttranslational modification, protein turnover, chaperones, Transcription];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1573864603 209 FWWPVAALIIAL----IIHEYSHGIQARAHGMQVRSFGL-----LLA----------GPLPVGAF-------------AE 256
Cdd:COG0750     3 FLLTILAFILVLgvlvFVHELGHFLVARLFGVKVEEFSIgfgpkLFSkkrgeteygiRAIPLGGYvkmagmdpesevaPE 82

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1573864603 257 PEYEEMIRAPRRERMRLYAAGPSINLLACWIVLILLsATATGFAATNDGVhaVG-IIEDTGAEDAGLKPYETITQINDVP 335
Cdd:COG0750    83 DDPRAFNSKPVWQRLIIVLAGPLANFLLAIVLFAVL-FMTVGVPVLTPPV--VGeVVPGSPAAKAGLQPGDRIVAINGQP 159

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1573864603 336 VIDYSSFTEVMSDfEAGDSATMTVltppsqgeveerlievvftdswdyhmnecrERENcdeaALEELLAKLKIKKGD--A 413
Cdd:COG0750   160 VTSWDDLVDIIRA-SPGKPLTLTV------------------------------ERDG----EELTLTVTPRLVEEDgvG 204

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1573864603 414 FLGVS-GLQSSTAAVDNWGYFfnddYDASEKVVGTIFAPLAMLGVPIALDGHTMNLeqramltAGDGAIASTLGTEGMLA 492
Cdd:COG0750   205 RIGVSpSGEVVTVRYGPLEAL----GAGVKETWDMIVLTLKGLGKLITGKVSAKNL-------SGPIGIAGIAGEAASSG 273

                         330       340       350
                  ....*....|....*....|....*....|..
gi 1573864603 493 AFDFLFWLAWINFLLGFANLIPMVPFDGGHLV 524
Cdd:COG0750   274 LASFLSFLALLSINLGVLNLLPIPALDGGHLL 305

permuted PDZ domain of Deg/high-temperature requirement factor A (HtrA) family of housekeeping serine proteases and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of Deg/HtrA-type serine proteases that participate in folding and degradation of aberrant proteins, and in processing and maturation of native proteins. Typically, these proteases have an N-terminal serine protease domain and at least one C-terminal PDZ domain that recognizes substrates, and in some cases activates the protease function. An exception is yeast Nma11p which has two protease domains and four PDZ domains; its N-terminal half is comprised of a protease domain, followed by two PDZ domains, and its C-terminal half has a similar domain arrangement. HtrA-type proteases include the human HtrA1-4 and MBTPS2, tricorn protease, DegS, DegP and C-terminal processing peptidase, cyanobacterial serine proteases Hhoa, HhoB, and HtrA, and yeast Nma11p. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-termini of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains and as well as those with circular permutations and domain swapping of beta-strands. The canonical PDZ domain contains six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2); arranged as A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F. This Deg/HtrA family PDZ domain is a circularly permuted PDZ domain which places beta-strand A at the C-terminus. Another permutation exists in the PDZ superfamily which places both beta-strands A and B on the C-terminus.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1573864603 283 LACWIVLILLSATATGFAATNDGVHAVGIIEDTGAEDAGLKPYETITQINDVPVIDYSSFTEVMSDFEAGDSATMTVL 360
Cdd:cd06779     4 LGIEMENISPLLAKELGLPVNRGVLVAEVIPGSPAAKAGLKEGDVILSVNGKPVTSFNDLRAALDTKKPGDSLNLTIL 81

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. SpoIVFB (sporulation protein, stage IV cell wall formation, F locus, promoter-distal B) 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.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1573864603 496 FLFWLAWINFLLGFANLIPMVPFDGGHLVRDgthsvikRVARKMDPLKAENLALRLSRMSSL 557
Cdd:cd06161   117 LLEFLAQVNLILGLFNLLPALPLDGGRVLRA-------LLWRRTGYRRATRIAARIGQLFAI 171

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
                  ....*....|....*....|....*....|..
gi 1573864603 494 FDFLFWLAWINFLLGFANLIPMVPFDGGHLVR 525
Cdd:cd05709   117 ANLLAFLALINLNLAVFNLLPIPPLDGGRILR 148

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 1573864603 197 LLLIPGVTSFVPFWWPVAALIIALI----------IHEYSHGIQARAHGMQVRSFGLllagpLPVGAFAepEYEEMIRAP 266
Cdd:cd06164    23 WSFGPGVFPAVPPALGAVAWLLGLAaalllfasvlLHELGHSLVARRYGIPVRSITL-----FLFGGVA--RLEREPETP 95

                          90       100       110
                  ....*....|....*....|....*....|....*
gi 1573864603 267 RRErMRLYAAGPSINL---LACWIVLILLSATATG 298
Cdd:cd06164    96 GQE-FVIAIAGPLVSLvlaLLFLLLSLALPGSGAG 129

periplasmic serine protease, Do/DeqQ family; This family consists of a set proteins various designated DegP, heat shock protein HtrA, and protease DO. The ortholog in Pseudomonas aeruginosa is designated MucD and is found in an operon that controls mucoid phenotype. This family also includes the DegQ (HhoA) paralog in E. coli which can rescue a DegP mutant, but not the smaller DegS paralog, which cannot. Members of this family are located in the periplasm and have separable functions as both protease and chaperone. Members have a trypsin domain and two copies of a PDZ domain. This protein protects bacteria from thermal and other stresses and may be important for the survival of bacterial pathogens.// The chaperone function is dominant at low temperatures, whereas the proteolytic activity is turned on at elevated temperatures. [Protein fate, Protein folding and stabilization, Protein fate, Degradation of proteins, peptides, and glycopeptides]

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1573864603 305 GVHAVGIIEDTGAEDAGLKPYETITQINDVPVIDYSSFTEVMSDFEAGDSATMTVL 360
Cdd:TIGR02037 258 GALVAQVLPGSPAEKAGLKAGDVITSVNGKPISSFADLRRAIGTLKPGKKVTLGIL 313

C-terminal processing protease CtpA/Prc, contains a PDZ domain [Posttranslational modification, protein turnover, chaperones];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1573864603 299 FAATNDGVHAVGIIEDTGAEDAGLKPYETITQINDVPVIDYsSFTEVMSDF--EAGDSATMTVLTPPSQGEVEERLI-EV 375
Cdd:COG0793    66 LGEEDGKVVVVSVIPGSPAEKAGIKPGDIILAIDGKSVAGL-TLDDAVKLLrgKAGTKVTLTIKRPGEGEPITVTLTrAE 144

                          90
                  ....*....|
gi 1573864603 376 VFTDSWDYHM 385
Cdd:COG0793   145 IKLPSVEAKL 154

Domain present in PSD-95, Dlg, and ZO-1/2; Also called DHR (Dlg homologous region) or GLGF (relatively well conserved tetrapeptide in these domains). Some PDZs have been shown to bind C-terminal polypeptides; others appear to bind internal (non-C-terminal) polypeptides. Different PDZs possess different binding specificities.

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1573864603  302 TNDGVHAVGIIEDTGAEDAGLKPYETITQINDVPVIDYSSFTEVMSDFEAGDSATMTVLTPP 363
Cdd:smart00228  24 EGGGVVVSSVVPGSPAAKAGLRVGDVILEVNGTSVEGLTHLEAVDLLKKAGGKVTLTVLRGG 85

circularly permuted PDZ domains of Escherichia coli Regulator of sigma-E protease (RseP) and related domains; Permuted PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of ResP (also known as Site-2 protease RseP, and YaeL), and related domains. RseP is involved in the regulation of an extracytoplasmic stress response through the cleavage of membrane-spanning anti-stress-response transcription factor (anti-sigmE) protein RseA; it cleaves the peptide bond between the critical alanine and cysteine in the transmembrane region of RseA, releasing the cytoplasmic domain of RseA with its associated sigmaE. RseP contains two tandem-arranged periplasmic PDZ domains (PDZ-N/PDZ1 and PDZ-C/PDZ2) which act to negatively regulate protease action on intact RseA; they serve as a size-exclusion filter which prevents the access of an intact RseA into the active site of RseP. PDZ domains usually bind in sequence-specific manner to short peptide sequences located at the C-terminal of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains and as well as those with circular permutations and domain swapping of beta-strands. The canonical PDZ domain contains six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2); arranged as beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F. This RseP family PDZ domain is a circularly permuted PDZ domain which places both beta-strands A and B at the C-terminus. Another permutation exists in the PDZ superfamily which places beta-strand A at the C-terminus.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1573864603 310 GIIEDTGAEDAGLKPYETITQINDVPVIDYSSFTEVMSDfEAGDSATMTVL 360
Cdd:cd23081     5 EVVANSPAAEAGLKPGDRILKIDGQKVRTWEDIVRIVRE-NPGKPLTLKIE 54

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
                  ....*....|....*....|....*....|....*....|.
gi 1573864603 489 GMLAAFDFLFW----LAWINFLLGFANLIPMVPFDGGHLVR 525
Cdd:cd06160   103 GLLLALPVLIIglavAGWVGLLVTALNLLPVGQLDGGHIVR 143