circularly permuted PDZ domain of membrane-bound transcription factor site-2 protease (MBTPS2, also known as S2P) and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of MBTPS2, also known as sterol regulatory element-binding protein (SREBP) Site-2 protease (S2P), and related domains. MBTPS2 is a zinc metalloprotease (MEROPS family M50A). In the Golgi, it catalyzes the second step in the proteolytic activation of sterol regulatory element-binding proteins (SREBPs), releasing the transcriptionally active N-terminal domain of SREBP, which then enters the nucleus and activates genes encoding the low density lipoprotein (LDL) receptor and enzymes for cholesterol and fatty acid biosynthesis. MBTPS2 also mediates the second step in the proteolytic activation of the cyclic AMP-dependent transcription factor ATF6. ATF6 is a membrane-bound transcription factor that activates genes in the endoplasmic reticulum (ER) stress response. PDZ domains usually bind in a 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 A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F. One permutation places beta-strand A on the C-terminus, another permutation places both beta-strands A and B on the C-terminus.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 291407207 223 IFCAGIWHNFVLALLGILALVLLPVILLPFYYTGVGVLITEVAEDSPAIGPRGLFVGDLVTHLQDCPVTNVQDWNECLDT 302
Cdd:cd06775    1 IYCAGVWHNFVLVLVALLVLFLLPFLLSPFYYTGSGVVVTEVVENSPVSGPRGLFVGDVITSINDCPVTSVEDWMKCLEE 80

                         90       100
                 ....*....|....*....|....*..
gi 291407207 303 IAYEPQIGYCISASTLQQLSFPVRAYK 329
Cdd:cd06775   81 VSKSPQSGYCVSADFLQQLDTSSRVYK 107

circularly permuted PDZ domain of membrane-bound transcription factor site-2 protease (MBTPS2, also known as S2P) and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of MBTPS2, also known as sterol regulatory element-binding protein (SREBP) Site-2 protease (S2P), and related domains. MBTPS2 is a zinc metalloprotease (MEROPS family M50A). In the Golgi, it catalyzes the second step in the proteolytic activation of sterol regulatory element-binding proteins (SREBPs), releasing the transcriptionally active N-terminal domain of SREBP, which then enters the nucleus and activates genes encoding the low density lipoprotein (LDL) receptor and enzymes for cholesterol and fatty acid biosynthesis. MBTPS2 also mediates the second step in the proteolytic activation of the cyclic AMP-dependent transcription factor ATF6. ATF6 is a membrane-bound transcription factor that activates genes in the endoplasmic reticulum (ER) stress response. PDZ domains usually bind in a 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 A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F. One permutation places beta-strand A on the C-terminus, another permutation places both beta-strands A and B on the C-terminus.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 291407207 223 IFCAGIWHNFVLALLGILALVLLPVILLPFYYTGVGVLITEVAEDSPAIGPRGLFVGDLVTHLQDCPVTNVQDWNECLDT 302
Cdd:cd06775    1 IYCAGVWHNFVLVLVALLVLFLLPFLLSPFYYTGSGVVVTEVVENSPVSGPRGLFVGDVITSINDCPVTSVEDWMKCLEE 80

                         90       100
                 ....*....|....*....|....*..
gi 291407207 303 IAYEPQIGYCISASTLQQLSFPVRAYK 329
Cdd:cd06775   81 VSKSPQSGYCVSADFLQQLDTSSRVYK 107

circularly permuted PDZ domain of membrane-bound transcription factor site-2 protease (MBTPS2, also known as S2P) and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of MBTPS2, also known as sterol regulatory element-binding protein (SREBP) Site-2 protease (S2P), and related domains. MBTPS2 is a zinc metalloprotease (MEROPS family M50A). In the Golgi, it catalyzes the second step in the proteolytic activation of sterol regulatory element-binding proteins (SREBPs), releasing the transcriptionally active N-terminal domain of SREBP, which then enters the nucleus and activates genes encoding the low density lipoprotein (LDL) receptor and enzymes for cholesterol and fatty acid biosynthesis. MBTPS2 also mediates the second step in the proteolytic activation of the cyclic AMP-dependent transcription factor ATF6. ATF6 is a membrane-bound transcription factor that activates genes in the endoplasmic reticulum (ER) stress response. PDZ domains usually bind in a 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 A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F. One permutation places beta-strand A on the C-terminus, another permutation places both beta-strands A and B on the C-terminus.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 291407207 223 IFCAGIWHNFVLALLGILALVLLPVILLPFYYTGVGVLITEVAEDSPAIGPRGLFVGDLVTHLQDCPVTNVQDWNECLDT 302
Cdd:cd06775    1 IYCAGVWHNFVLVLVALLVLFLLPFLLSPFYYTGSGVVVTEVVENSPVSGPRGLFVGDVITSINDCPVTSVEDWMKCLEE 80

                         90       100
                 ....*....|....*....|....*..
gi 291407207 303 IAYEPQIGYCISASTLQQLSFPVRAYK 329
Cdd:cd06775   81 VSKSPQSGYCVSADFLQQLDTSSRVYK 107

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 291407207  38 LENNGLSISPFHIRWQTAvfNRAFYSWGRRKARmLYQWF-NFGMVFGVIAMFSSFFLLGKTLMQTLAQMMADSpssysss 116
Cdd:cd06159   23 LEYNISTYGPFLMLRTKK--GRGFIDKLARPKR-FWRAFgNIGIPIAFVGMIFMLLLILLSAIIILSGPPAPL------- 92

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 291407207 117 sssssssssassssssssssssslhNEQVLQVVVPGINLPVnQLTYFFAAVLISGVVHEIGHGIAAIREQVRFNGFGIFL 196
Cdd:cd06159   93 -------------------------NAPRNVLVIPGVNIFI-PLPYGIIALVVGVVVHELSHGILARVEGIKVKSGGLLL 146

                        170       180       190
                 ....*....|....*....|....*....|....*.
gi 291407207 197 FIIYPGAFVDLFTTHLQLISPVQQLRIFCAGIWHNF 232
Cdd:cd06159  147 LIIPPGAFVEPDEEELNKADRRIRLRIFAAGVTANF 182

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 291407207 162 YFFAAVLISGVVHEIGHGIAAIREQVRFNGFGIFL-------------FIIYPGAFVDLFTTHLQL--ISPVQQLRIFCA 226
Cdd:cd05709    2 AFILALLISVTVHELGHALVARRLGVKVARFSGGFtlnplkhgdpygiILIPLGGYAKPVGENPRAfkKPRWQRLLVALA 81

                 ....*.
gi 291407207 227 GIWHNF 232
Cdd:cd05709   82 GPLANL 87

PDZ domain 4 of Discs Large 5 (Dlg5) and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain 4 of Drosophila and mammalian Dlg5, and related domains. Dlg5 is a scaffold protein with multiple conserved functions that are independent of each other in regulating growth, cell polarity, and cell adhesion. It has a coiled-coil domain, 4 PDZ domains and a MAGUK domain (an SH3 domain next to a non-catalytically active guanylate kinase domain). Deregulation of Dlg5 has been implicated in the malignancy of several cancer types. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This Dlg5-like family PDZ4 domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

                         10        20
                 ....*....|....*....|....*.
gi 291407207 257 VGVLITEVAEDSPAIGPRGLFVGDLV 282
Cdd:cd06766   24 HGIFVEDVEDDSPAKGPDGLVPGDLI 49