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 15239226 299 SAFDNLELLKDGLPGALVTALVLGVHELGHILVANSLGIKLGVPFFVPSWQIGSFGAITRIKNIVAKREDLLKVAAAGPL 378
Cdd:cd06160  22 DVPGNPLLLLQGLPFALALLAILGIHEMGHYLAARRHGVKASLPYFIPFPFIGTFGAFIRMRSPIPNRKALFDIALAGPL 101

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15239226 379 AGFslglilfliglfvppsdGIGVVVdasvfhesflaggiakLLLGdalkegtsislnpLVIWAWAGLLINGINSIPAGE 458
Cdd:cd06160 102 AGL-----------------LLALPV----------------LIIG-------------LAVAGWVGLLVTALNLLPVGQ 135

                       170       180       190       200
                ....*....|....*....|....*....|....*....|....*...
gi 15239226 459 LDGGKIAFSIWGRKTATRLTGASIALLGLSALFSDVA--FYWVVLIFF 504
Cdd:cd06160 136 LDGGHIVRALFGRRVAALIGIGLLVALGLLALYLSFSiwLLWALLLLI 183

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 15239226 299 SAFDNLELLKDGLPGALVTALVLGVHELGHILVANSLGIKLGVPFFVPSWQIGSFGAITRIKNIVAKREDLLKVAAAGPL 378
Cdd:cd06160  22 DVPGNPLLLLQGLPFALALLAILGIHEMGHYLAARRHGVKASLPYFIPFPFIGTFGAFIRMRSPIPNRKALFDIALAGPL 101

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15239226 379 AGFslglilfliglfvppsdGIGVVVdasvfhesflaggiakLLLGdalkegtsislnpLVIWAWAGLLINGINSIPAGE 458
Cdd:cd06160 102 AGL-----------------LLALPV----------------LIIG-------------LAVAGWVGLLVTALNLLPVGQ 135

                       170       180       190       200
                ....*....|....*....|....*....|....*....|....*...
gi 15239226 459 LDGGKIAFSIWGRKTATRLTGASIALLGLSALFSDVA--FYWVVLIFF 504
Cdd:cd06160 136 LDGGHIVRALFGRRVAALIGIGLLVALGLLALYLSFSiwLLWALLLLI 183

Peptidase family M50;

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 15239226   312 PGALVTALVLGVHELGHILVANSLGIKLGVpFFVPSWQIGS--FGAITRIKNIVAKRE--DLLKVAAAGPLAGF 381
Cdd:pfam02163   1 AFILALGILVVVHELGHFLVARRFGVKVER-FSIGFYRIALipLGGYVKMADEFKSKSpwQRLAIALAGPLANF 73

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 15239226 299 SAFDNLELLKDGLPGALVTALVLGVHELGHILVANSLGIKLGVPFFVPSWQIGSFGAITRIKNIVAKREDLLKVAAAGPL 378
Cdd:cd06160  22 DVPGNPLLLLQGLPFALALLAILGIHEMGHYLAARRHGVKASLPYFIPFPFIGTFGAFIRMRSPIPNRKALFDIALAGPL 101

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15239226 379 AGFslglilfliglfvppsdGIGVVVdasvfhesflaggiakLLLGdalkegtsislnpLVIWAWAGLLINGINSIPAGE 458
Cdd:cd06160 102 AGL-----------------LLALPV----------------LIIG-------------LAVAGWVGLLVTALNLLPVGQ 135

                       170       180       190       200
                ....*....|....*....|....*....|....*....|....*...
gi 15239226 459 LDGGKIAFSIWGRKTATRLTGASIALLGLSALFSDVA--FYWVVLIFF 504
Cdd:cd06160 136 LDGGHIVRALFGRRVAALIGIGLLVALGLLALYLSFSiwLLWALLLLI 183

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 15239226 311 LPGALVTALVLGVHELGHILVANSLGIKLGVPFFVPSWQIGS-----------FGAITRIKNIV-----AKREDLLKVAA 374
Cdd:cd05709   1 LAFILALLISVTVHELGHALVARRLGVKVARFSGGFTLNPLKhgdpygiilipLGGYAKPVGENprafkKPRWQRLLVAL 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15239226 375 AGPLAGFslglilfliglfvppsdGIGVVVdASVFhesFLAGGIAKLLLGDALKEGtsiSLNPLVIWAWAGLLINGINSI 454
Cdd:cd05709  81 AGPLANL-----------------LLALLL-LLLL---LLLGGLPPAPVGQAASSG---LANLLAFLALINLNLAVFNLL 136

                       170       180       190       200
                ....*....|....*....|....*....|....*....|.
gi 15239226 455 PAGELDGGKIAFSIWGRKTATRLTGAS----IALLGLSALF 491
Cdd:cd05709 137 PIPPLDGGRILRALLEAIRGRVEERLEaygfAILLGLLLLL 177

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 15239226 314 ALVTALVLGV----HELGHILVANSLGIKlgvpffVPSWQIGSFGAITRIKNIVAKREDLLKVAAAGPLAgfslglilfl 389
Cdd:cd06164  45 GLAAALLLFAsvllHELGHSLVARRYGIP------VRSITLFLFGGVARLEREPETPGQEFVIAIAGPLV---------- 108

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15239226 390 iglfvppsdgigvvvdasvfheSFLAGGIAkLLLGDALKEGTSISLNPLVIW-AWAGLLINGINSIPAGELDGGKIAFSI 468
Cdd:cd06164 109 ----------------------SLVLALLF-LLLSLALPGSGAGPLGVLLGYlALINLLLAVFNLLPAFPLDGGRVLRAL 165

                       170       180       190       200       210
                ....*....|....*....|....*....|....*....|....*....|....
gi 15239226 469 WGRKTATRLTGASIA---------LLGLSALFSDVAFY----WVVLI-FFLQRG 508
Cdd:cd06164 166 LWRRTGDYLKATRIAawvgrgfavLLIILGLLSLFLNLlgglWLILIaWFLYIG 219