Rhomboid family; This family contains integral membrane proteins that are related to Drosophila rhomboid protein. Members of this family are found in bacteria and eukaryotes. Rhomboid promotes the cleavage of the membrane-anchored TGF-alpha-like growth factor Spitz, allowing it to activate the Drosophila EGF receptor. Analysis has shown that Rhomboid-1 is an intramembrane serine protease (EC:3.4.21.105). Parasite-encoded rhomboid enzymes are also important for invasion of host cells by Toxoplasma and the malaria parasite.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564373428  205 PQLRAQAWRYVTYIFMHAGVEQLGLNVALQLLVGVPLEMVHGATRIGLVYVAGVVAGSLAVSVADM-TAPVVGSSGGVYA 283
Cdd:pfam01694   1 PVQPGQLWRLITSMFLHAGWLHLLFNMLALLFFGGPLERILGSVRFLLLYLLSGIAGSLLSYLFSPlSTPSVGASGAIFG 80

                          90       100       110
                  ....*....|....*....|....*....|
gi 564373428  284 LVSAHLANIVMNWSGMKCQFKLLRMAVALI 313
Cdd:pfam01694  81 LLGALLVLGPRNRILLFGLIGALLALLLFI 110

Rhomboid family; This family contains integral membrane proteins that are related to Drosophila rhomboid protein. Members of this family are found in bacteria and eukaryotes. Rhomboid promotes the cleavage of the membrane-anchored TGF-alpha-like growth factor Spitz, allowing it to activate the Drosophila EGF receptor. Analysis has shown that Rhomboid-1 is an intramembrane serine protease (EC:3.4.21.105). Parasite-encoded rhomboid enzymes are also important for invasion of host cells by Toxoplasma and the malaria parasite.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564373428  205 PQLRAQAWRYVTYIFMHAGVEQLGLNVALQLLVGVPLEMVHGATRIGLVYVAGVVAGSLAVSVADM-TAPVVGSSGGVYA 283
Cdd:pfam01694   1 PVQPGQLWRLITSMFLHAGWLHLLFNMLALLFFGGPLERILGSVRFLLLYLLSGIAGSLLSYLFSPlSTPSVGASGAIFG 80

                          90       100       110
                  ....*....|....*....|....*....|
gi 564373428  284 LVSAHLANIVMNWSGMKCQFKLLRMAVALI 313
Cdd:pfam01694  81 LLGALLVLGPRNRILLFGLIGALLALLLFI 110

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 564373428   36 EDHWKVLFEKFDPGSTGYISTGKFRSLLESHSSKLDPHKKEV--LLALADSHADGQICYQDFVNLMS 100
Cdd:pfam13499   1 EEKLKEAFKLLDSDGDGYLDVEELKKLLRKLEEGEPLSDEEVeeLFKEFDLDKDGRISFEEFLELYS 67

Penta-EF hand, calcium binding motifs, found in Drosophila melanogaster calpain-A (CalpA), calpain-B (CalpB), and similar proteins; The family contains two calpains that have been found in Drosophila, CalpA and CalpB. CalpA, also termed calcium-activated neutral proteinase A (CANP A), or calpain-A catalytic subunit, is a Drosophila calpain homolog specifically expressed in a few neurons in the central nervous system, in scattered endocrine cells in the midgut, and in blood cells. CalpB, also termed calcium-activated neutral proteinase B (CANP B), contains calpain-B catalytic subunit 1 and calpain-B catalytic subunit 2. Both CalpA and CalpB are closely related to that of vertebrate calpains, and they share similar domain architecture, which consists of four domains: the N-terminal domain I, the catalytic domain II carrying the three active site residues, Cys, His and Asn, the Ca2+-regulated phospholipid-binding domain III, and penta-EF-hand Ca2+-binding domain IV. Besides, CalpA and CalpB display some distinguishing structural features that are not found in mammalian typical calpains. CalpA harbors a 76 amino acid long hydrophobic stretch inserted in domain IV, which may be involved in membrane attachment of this enzyme. CalpB has an unusually long N-terminal tail of 224 amino acids, which belongs to the class of intrinsically unstructured proteins (IUP) and may become ordered upon binding to target protein(s). Moreover, they do not need small regulatory subunits for their catalytic activity, and their proteolytic function is not regulated by an intrinsic inhibitor as the Drosophila genome contains neither regulatory subunit nor calpastatin orthologs. As a result, they may exist as a monomer or perhaps as a homo- or heterodimer together with a second large subunit. Furthermore, both CalpA and CalpB are dispensable for viability and fertility and do not share vital functions during Drosophila development. Phosphatidylinositol 4,5-diphosphate, phosphatidylinositol 4-monophosphate, phosphatidylinositol, and phosphatidic acid can stimulate the activity and the rate of activation of CalpA, but not CalpB. Calpain A modulates Toll responses by limited Cactus/IkappaB proteolysis. CalpB directly interacts with talin, an important component of the focal adhesion complex, and functions as an important modulator in border cell migration within egg chambers, which may act via the digestion of talin. CalpB can be phosphorylated by cAMP-dependent protein kinase (protein kinase A, PKA; EC 2.7.11.11) at Ser240 and Ser845, as well as by mitogen-activated protein kinase (ERK1 and ERK2; EC 2.7.11.24) at Thr747. The activation of the ERK pathway by extracellular signals results in the phosphorylation and activation of calpain B. In Schneider cells (S2), calpain B was mainly in the cytoplasm and upon a rise in Ca2+ the enzyme adhered to intracellular membranes.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 564373428  38 HWKVLFEKFDPGSTGYISTGKFRSLLESHSSKLDPHkkeVLLALAD--SHADGQICYQDFVNLM 99
Cdd:cd16196   72 SWKRVFKLFDTDGSGSFSSFELRNALNSAGFRLSNA---TLNALVLrySNKDGRISFDDFIMCA 132

Ca2+-binding protein, EF-hand superfamily [Signal transduction mechanisms];

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 564373428  42 LFEKFDPGSTGYISTGKFRSLLESHssKLDPHKKEVLLALADSHADGQICYQDFVNLM 99
Cdd:COG5126   74 AFDLLDTDGDGKISADEFRRLLTAL--GVSEEEADELFARLDTDGDGKISFEEFVAAV 129

Rhomboid family; This family contains integral membrane proteins that are related to Drosophila rhomboid protein. Members of this family are found in bacteria and eukaryotes. Rhomboid promotes the cleavage of the membrane-anchored TGF-alpha-like growth factor Spitz, allowing it to activate the Drosophila EGF receptor. Analysis has shown that Rhomboid-1 is an intramembrane serine protease (EC:3.4.21.105). Parasite-encoded rhomboid enzymes are also important for invasion of host cells by Toxoplasma and the malaria parasite.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564373428  205 PQLRAQAWRYVTYIFMHAGVEQLGLNVALQLLVGVPLEMVHGATRIGLVYVAGVVAGSLAVSVADM-TAPVVGSSGGVYA 283
Cdd:pfam01694   1 PVQPGQLWRLITSMFLHAGWLHLLFNMLALLFFGGPLERILGSVRFLLLYLLSGIAGSLLSYLFSPlSTPSVGASGAIFG 80

                          90       100       110
                  ....*....|....*....|....*....|
gi 564373428  284 LVSAHLANIVMNWSGMKCQFKLLRMAVALI 313
Cdd:pfam01694  81 LLGALLVLGPRNRILLFGLIGALLALLLFI 110

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 564373428   36 EDHWKVLFEKFDPGSTGYISTGKFRSLLESHSSKLDPHKKEV--LLALADSHADGQICYQDFVNLMS 100
Cdd:pfam13499   1 EEKLKEAFKLLDSDGDGYLDVEELKKLLRKLEEGEPLSDEEVeeLFKEFDLDKDGRISFEEFLELYS 67

Penta-EF hand, calcium binding motifs, found in Drosophila melanogaster calpain-A (CalpA), calpain-B (CalpB), and similar proteins; The family contains two calpains that have been found in Drosophila, CalpA and CalpB. CalpA, also termed calcium-activated neutral proteinase A (CANP A), or calpain-A catalytic subunit, is a Drosophila calpain homolog specifically expressed in a few neurons in the central nervous system, in scattered endocrine cells in the midgut, and in blood cells. CalpB, also termed calcium-activated neutral proteinase B (CANP B), contains calpain-B catalytic subunit 1 and calpain-B catalytic subunit 2. Both CalpA and CalpB are closely related to that of vertebrate calpains, and they share similar domain architecture, which consists of four domains: the N-terminal domain I, the catalytic domain II carrying the three active site residues, Cys, His and Asn, the Ca2+-regulated phospholipid-binding domain III, and penta-EF-hand Ca2+-binding domain IV. Besides, CalpA and CalpB display some distinguishing structural features that are not found in mammalian typical calpains. CalpA harbors a 76 amino acid long hydrophobic stretch inserted in domain IV, which may be involved in membrane attachment of this enzyme. CalpB has an unusually long N-terminal tail of 224 amino acids, which belongs to the class of intrinsically unstructured proteins (IUP) and may become ordered upon binding to target protein(s). Moreover, they do not need small regulatory subunits for their catalytic activity, and their proteolytic function is not regulated by an intrinsic inhibitor as the Drosophila genome contains neither regulatory subunit nor calpastatin orthologs. As a result, they may exist as a monomer or perhaps as a homo- or heterodimer together with a second large subunit. Furthermore, both CalpA and CalpB are dispensable for viability and fertility and do not share vital functions during Drosophila development. Phosphatidylinositol 4,5-diphosphate, phosphatidylinositol 4-monophosphate, phosphatidylinositol, and phosphatidic acid can stimulate the activity and the rate of activation of CalpA, but not CalpB. Calpain A modulates Toll responses by limited Cactus/IkappaB proteolysis. CalpB directly interacts with talin, an important component of the focal adhesion complex, and functions as an important modulator in border cell migration within egg chambers, which may act via the digestion of talin. CalpB can be phosphorylated by cAMP-dependent protein kinase (protein kinase A, PKA; EC 2.7.11.11) at Ser240 and Ser845, as well as by mitogen-activated protein kinase (ERK1 and ERK2; EC 2.7.11.24) at Thr747. The activation of the ERK pathway by extracellular signals results in the phosphorylation and activation of calpain B. In Schneider cells (S2), calpain B was mainly in the cytoplasm and upon a rise in Ca2+ the enzyme adhered to intracellular membranes.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 564373428  38 HWKVLFEKFDPGSTGYISTGKFRSLLESHSSKLDPHkkeVLLALAD--SHADGQICYQDFVNLM 99
Cdd:cd16196   72 SWKRVFKLFDTDGSGSFSSFELRNALNSAGFRLSNA---TLNALVLrySNKDGRISFDDFIMCA 132

rhomboid-1 protease; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564373428 208 RAQAWRYVTYIFMHAGVEQLGLNVALQLLVGVPLEMVHGATRIGLVYVAGVVAGSLAVSVADMTAPVVGSSGGVYALVSA 287
Cdd:PTZ00101  99 QGEIHRLILPIFLHANIFHTFFNVFFQLRMGFTLEKNYGIVKIIILYFLTGIYGNILSSSVTYCPIKVGASTSGMGLLGI 178

                         90
                 ....*....|...
gi 564373428 288 HLANIVMNWSGMK 300
Cdd:PTZ00101 179 VTSELILLWHVIR 191

EF-hand domain; This domain is found predominantly in DJ binding proteins.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564373428   30 RLPAAPEDHWKVL---FEKFDPGSTGYISTGKFRSLLESHSSKLDPHKKEVLLALADSHADGQICYQDFVNLMSNKRSNS 106
Cdd:pfam08976  10 RLHKAVASHYHAItqeFENFDTLKSNTISRDEFRAICNRHIQILTDEQFDRLWNELPVNAKGRLKYPDFLSKFSIERTAA 89

S-100: S-100 domain, which represents the largest family within the superfamily of proteins carrying the Ca-binding EF-hand motif. Note that this S-100 hierarchy contains only S-100 EF-hand domains, other EF-hands have been modeled separately. S100 proteins are expressed exclusively in vertebrates, and are implicated in intracellular and extracellular regulatory activities. Intracellularly, S100 proteins act as Ca-signaling or Ca-buffering proteins. The most unusual characteristic of certain S100 proteins is their occurrence in extracellular space, where they act in a cytokine-like manner through RAGE, the receptor for advanced glycation products. Structural data suggest that many S100 members exist within cells as homo- or heterodimers and even oligomers; oligomerization contributes to their functional diversification. Upon binding calcium, most S100 proteins change conformation to a more open structure exposing a hydrophobic cleft. This hydrophobic surface represents the interaction site of S100 proteins with their target proteins. There is experimental evidence showing that many S100 proteins have multiple binding partners with diverse mode of interaction with different targets. In addition to S100 proteins (such as S100A1,-3,-4,-6,-7,-10,-11,and -13), this group includes the ''fused'' gene family, a group of calcium binding S100-related proteins. The ''fused'' gene family includes multifunctional epidermal differentiation proteins - profilaggrin, trichohyalin, repetin, hornerin, and cornulin; functionally these proteins are associated with keratin intermediate filaments and partially crosslinked to the cell envelope. These ''fused'' gene proteins contain N-terminal sequence with two Ca-binding EF-hands motif, which may be associated with calcium signaling in epidermal cells and autoprocessing in a calcium-dependent manner. In contrast to S100 proteins, "fused" gene family proteins contain an extraordinary high number of almost perfect peptide repeats with regular array of polar and charged residues similar to many known cell envelope proteins.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 564373428  49 GSTGYISTGKFRSLLESH-----SSKLDPHKKEVLLALADSHADGQICYQDFVNLM 99
Cdd:cd00213   22 GDKDTLSKKELKELLETElpnflKNQKDPEAVDKIMKDLDVNKDGKVDFQEFLVLI 77