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 334187443 267 SAFDNLELLKDGLPGALVTALVLGVHELGHILVANSLGIKLGVPFFVPSWQIGSFGAITRIKNIVAKREDLLKVAAAGPL 346
Cdd:cd06160   22 DVPGNPLLLLQGLPFALALLAILGIHEMGHYLAARRHGVKASLPYFIPFPFIGTFGAFIRMRSPIPNRKALFDIALAGPL 101

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 334187443 347 AGFslglilfliglfvppsdGIGVVVdasvfhesflaggiakLLLGdalkegtsislnpLVIWAWAGLLINGINSIPAGE 426
Cdd:cd06160  102 AGL-----------------LLALPV----------------LIIG-------------LAVAGWVGLLVTALNLLPVGQ 135

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|....*...
gi 334187443 427 LDGGKIAFSIWGRKTATRLTGASIALLGLSALFSDVA--FYWVVLIFF 472
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 334187443 267 SAFDNLELLKDGLPGALVTALVLGVHELGHILVANSLGIKLGVPFFVPSWQIGSFGAITRIKNIVAKREDLLKVAAAGPL 346
Cdd:cd06160   22 DVPGNPLLLLQGLPFALALLAILGIHEMGHYLAARRHGVKASLPYFIPFPFIGTFGAFIRMRSPIPNRKALFDIALAGPL 101

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 334187443 347 AGFslglilfliglfvppsdGIGVVVdasvfhesflaggiakLLLGdalkegtsislnpLVIWAWAGLLINGINSIPAGE 426
Cdd:cd06160  102 AGL-----------------LLALPV----------------LIIG-------------LAVAGWVGLLVTALNLLPVGQ 135

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|....*...
gi 334187443 427 LDGGKIAFSIWGRKTATRLTGASIALLGLSALFSDVA--FYWVVLIFF 472
Cdd:cd06160  136 LDGGHIVRALFGRRVAALIGIGLLVALGLLALYLSFSiwLLWALLLLI 183

Peptidase family M50;

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 334187443  280 PGALVTALVLGVHELGHILVANSLGIKLGVpFFVPSWQIGS--FGAITRIKNIVAKRE--DLLKVAAAGPLAGF 349
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 334187443 267 SAFDNLELLKDGLPGALVTALVLGVHELGHILVANSLGIKLGVPFFVPSWQIGSFGAITRIKNIVAKREDLLKVAAAGPL 346
Cdd:cd06160   22 DVPGNPLLLLQGLPFALALLAILGIHEMGHYLAARRHGVKASLPYFIPFPFIGTFGAFIRMRSPIPNRKALFDIALAGPL 101

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 334187443 347 AGFslglilfliglfvppsdGIGVVVdasvfhesflaggiakLLLGdalkegtsislnpLVIWAWAGLLINGINSIPAGE 426
Cdd:cd06160  102 AGL-----------------LLALPV----------------LIIG-------------LAVAGWVGLLVTALNLLPVGQ 135

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|....*...
gi 334187443 427 LDGGKIAFSIWGRKTATRLTGASIALLGLSALFSDVA--FYWVVLIFF 472
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 334187443 279 LPGALVTALVLGVHELGHILVANSLGIKLGVPFFVPSWQIGS-----------FGAITRIKNIV-----AKREDLLKVAA 342
Cdd:cd05709    1 LAFILALLISVTVHELGHALVARRLGVKVARFSGGFTLNPLKhgdpygiilipLGGYAKPVGENprafkKPRWQRLLVAL 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 334187443 343 AGPLAGFslglilfliglfvppsdGIGVVVdASVFhesFLAGGIAKLLLGDALKEGtsiSLNPLVIWAWAGLLINGINSI 422
Cdd:cd05709   81 AGPLANL-----------------LLALLL-LLLL---LLLGGLPPAPVGQAASSG---LANLLAFLALINLNLAVFNLL 136

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|.
gi 334187443 423 PAGELDGGKIAFSIWGRKTATRLTGAS----IALLGLSALF 459
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 334187443 282 ALVTALVLGV----HELGHILVANSLGIKlgvpffVPSWQIGSFGAITRIKNIVAKREDLLKVAAAGPLAgfslglilfl 357
Cdd:cd06164   45 GLAAALLLFAsvllHELGHSLVARRYGIP------VRSITLFLFGGVARLEREPETPGQEFVIAIAGPLV---------- 108

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 334187443 358 iglfvppsdgigvvvdasvfheSFLAGGIAkLLLGDALKEGTSISLNPLVIW-AWAGLLINGINSIPAGELDGGKIAFSI 436
Cdd:cd06164  109 ----------------------SLVLALLF-LLLSLALPGSGAGPLGVLLGYlALINLLLAVFNLLPAFPLDGGRVLRAL 165

                        170       180       190       200       210
                 ....*....|....*....|....*....|....*....|....*....|....
gi 334187443 437 WGRKTATRLTGASIA---------LLGLSALFSDVAFY----WVVLI-FFLQRG 476
Cdd:cd06164  166 LWRRTGDYLKATRIAawvgrgfavLLIILGLLSLFLNLlgglWLILIaWFLYIG 219