Peptidase M48C Ste24p bepA-like, integral membrane protein; This family contains peptidase M48C Ste24p protease bepA (formerly yfgC)-like proteins considered to be putative metallopeptidases, containing a zinc-binding motif, HEXXH, and a COOH-terminal ER retrieval signal (KKXX). They proteolytically remove the C-terminal three residues of farnesylated proteins. They are integral membrane proteins associated with the endoplasmic reticulum and golgi, binding one zinc ion per subunit. In eukaryotes, Ste24p is required for the first NH2-terminal proteolytic processing event within the a-factor precursor, which takes place after COOH-terminal CAAX modification (C is cysteine; A is usually aliphatic; X is one of several amino acids) is complete. Mutation studies have shown that the HEXXH protease motif, which is extracellular but adjacent to a transmembrane domain and therefore close to the membrane surface, is critical for Ste24p activity. Several members of this family also contain tetratricopeptide (TPR) repeat motifs, which are involved in a variety of functions including protein-protein interactions. BepA has been shown to possess protease activity and is responsible for the degradation of incorrectly folded LptD, an essential outer-membrane protein (OMP) involved in OM transport and assembly of lipopolysaccharide. Overexpression of the bepA protease causes abnormal biofilm architecture.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 931484038  28 EVEIGKEVVKDVESKERVLNNAQVQRYVTNVGRKIANVCDRRDVKYSFKVLDSEEINAFACPGGYIYIYKGLMKQMDNEA 107
Cdd:cd07333    2 EVELGKQFAQQIRQQLPLVEDPEVNEYVNRIGQRLAAVSPRPPFPYRFFVVNDDSINAFATPGGYIYVNTGLILAADNEA 81

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 931484038 108 QLAAVLAHEVGHVVARHSAKRIQAvygysiamevalgdkmsatarqlvdaatglillGYGRENEYEADNYGILYAKNAGY 187
Cdd:cd07333   82 ELAGVLAHEIGHVVARHIAKQIEK---------------------------------SYSREDEREADQLGLQYLTKAGY 128

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|....*.
gi 931484038 188 NPKGMIQIFQKFKQMEGKPPSTFEKLLMSHPPASDRIGNGNKQIQK 233
Cdd:cd07333  129 DPRGMVSFFKKLRRKEWFGGSSIPTYLSTHPAPAERIAYLEELIAS 174

Peptidase M48C Ste24p bepA-like, integral membrane protein; This family contains peptidase M48C Ste24p protease bepA (formerly yfgC)-like proteins considered to be putative metallopeptidases, containing a zinc-binding motif, HEXXH, and a COOH-terminal ER retrieval signal (KKXX). They proteolytically remove the C-terminal three residues of farnesylated proteins. They are integral membrane proteins associated with the endoplasmic reticulum and golgi, binding one zinc ion per subunit. In eukaryotes, Ste24p is required for the first NH2-terminal proteolytic processing event within the a-factor precursor, which takes place after COOH-terminal CAAX modification (C is cysteine; A is usually aliphatic; X is one of several amino acids) is complete. Mutation studies have shown that the HEXXH protease motif, which is extracellular but adjacent to a transmembrane domain and therefore close to the membrane surface, is critical for Ste24p activity. Several members of this family also contain tetratricopeptide (TPR) repeat motifs, which are involved in a variety of functions including protein-protein interactions. BepA has been shown to possess protease activity and is responsible for the degradation of incorrectly folded LptD, an essential outer-membrane protein (OMP) involved in OM transport and assembly of lipopolysaccharide. Overexpression of the bepA protease causes abnormal biofilm architecture.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 931484038  28 EVEIGKEVVKDVESKERVLNNAQVQRYVTNVGRKIANVCDRRDVKYSFKVLDSEEINAFACPGGYIYIYKGLMKQMDNEA 107
Cdd:cd07333    2 EVELGKQFAQQIRQQLPLVEDPEVNEYVNRIGQRLAAVSPRPPFPYRFFVVNDDSINAFATPGGYIYVNTGLILAADNEA 81

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 931484038 108 QLAAVLAHEVGHVVARHSAKRIQAvygysiamevalgdkmsatarqlvdaatglillGYGRENEYEADNYGILYAKNAGY 187
Cdd:cd07333   82 ELAGVLAHEIGHVVARHIAKQIEK---------------------------------SYSREDEREADQLGLQYLTKAGY 128

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|....*.
gi 931484038 188 NPKGMIQIFQKFKQMEGKPPSTFEKLLMSHPPASDRIGNGNKQIQK 233
Cdd:cd07333  129 DPRGMVSFFKKLRRKEWFGGSSIPTYLSTHPAPAERIAYLEELIAS 174

Peptidase family M48; Peptidase_M48 is the largely extracellular catalytic region of CAAX prenyl protease homologs such as Human FACE-1 protease. These are metallopeptidases, with the characteriztic HExxH motif giving the two histidine-zinc-ligands and an adjacent glutamate on the next helix being the third. The whole molecule folds to form a deep groove/cleft into which the substrate can fit.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 931484038   46 LNNAQVQRyvtnVGRKIANVCDRRDVKYSFKVL-DSEEINAFAC---PGGYIYIYKGLMKQMDNEAQLAAVLAHEVGHVV 121
Cdd:pfam01435   2 LRNAELQR----VVERLAAAAGLPLPPWYVVVIkSSPVPNAFAYgllPGGRVVVTTGLLDLLETEDELAAVLGHEIGHIK 77

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 931484038  122 ARHSAKRIQAVYGYSIAM---------EVALGDKMSATARQL----VDAATGLILLGYGRENEYEADNYGILYAKNAGYN 188
Cdd:pfam01435  78 ARHSVESLSIMGGLSLAQlflallllgAAASGFANFGIIFLLligpLAALLTLLLLPYSRAQEYEADRLGAELMARAGYD 157

                         170       180       190
                  ....*....|....*....|....*....|....*..
gi 931484038  189 PKGMIQIFQKFKQM-EGKPPSTFEKLLMSHPPASDRI 224
Cdd:pfam01435 158 PRALIKLWGEIDNNgRASDGALYPELLSTHPSLVERI 194

Peptidase M48C Ste24p bepA-like, integral membrane protein; This family contains peptidase M48C Ste24p protease bepA (formerly yfgC)-like proteins considered to be putative metallopeptidases, containing a zinc-binding motif, HEXXH, and a COOH-terminal ER retrieval signal (KKXX). They proteolytically remove the C-terminal three residues of farnesylated proteins. They are integral membrane proteins associated with the endoplasmic reticulum and golgi, binding one zinc ion per subunit. In eukaryotes, Ste24p is required for the first NH2-terminal proteolytic processing event within the a-factor precursor, which takes place after COOH-terminal CAAX modification (C is cysteine; A is usually aliphatic; X is one of several amino acids) is complete. Mutation studies have shown that the HEXXH protease motif, which is extracellular but adjacent to a transmembrane domain and therefore close to the membrane surface, is critical for Ste24p activity. Several members of this family also contain tetratricopeptide (TPR) repeat motifs, which are involved in a variety of functions including protein-protein interactions. BepA has been shown to possess protease activity and is responsible for the degradation of incorrectly folded LptD, an essential outer-membrane protein (OMP) involved in OM transport and assembly of lipopolysaccharide. Overexpression of the bepA protease causes abnormal biofilm architecture.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 931484038  28 EVEIGKEVVKDVESKERVLNNAQVQRYVTNVGRKIANVCDRRDVKYSFKVLDSEEINAFACPGGYIYIYKGLMKQMDNEA 107
Cdd:cd07333    2 EVELGKQFAQQIRQQLPLVEDPEVNEYVNRIGQRLAAVSPRPPFPYRFFVVNDDSINAFATPGGYIYVNTGLILAADNEA 81

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 931484038 108 QLAAVLAHEVGHVVARHSAKRIQAvygysiamevalgdkmsatarqlvdaatglillGYGRENEYEADNYGILYAKNAGY 187
Cdd:cd07333   82 ELAGVLAHEIGHVVARHIAKQIEK---------------------------------SYSREDEREADQLGLQYLTKAGY 128

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|....*.
gi 931484038 188 NPKGMIQIFQKFKQMEGKPPSTFEKLLMSHPPASDRIGNGNKQIQK 233
Cdd:cd07333  129 DPRGMVSFFKKLRRKEWFGGSSIPTYLSTHPAPAERIAYLEELIAS 174

Oma1 peptidase-like, integral membrane metallopeptidase; This family contains peptidase M48 subfamily C (also known as Oma1 peptidase or mitochondrial metalloendopeptidase OMA1), including similar peptidases containing tetratricopeptide (TPR) repeats, as well as uncharacterized proteins such as E. coli bepA (formerly yfgC), ycaL and loiP (formerly yggG), considered to be putative metallopeptidases. Oma1 peptidase is part of the quality control system in the inner membrane of mitochondria, with its catalytic site facing the matrix space. It cleaves and thereby promotes the turnover of mistranslated or misfolded membrane proteins. Oma1 can cleave the misfolded multi-pass membrane protein Oxa1, thus exerting a function similar to the ATP-dependent m-AAA protease for quality control of inner membrane proteins. It has been proposed that in the absence of m-AAA protease, proteolysis of Oxa1 is mediated by Oma1 in an ATP-independent manner. Homologs of Oma1 are present in higher eukaryotes, eubacteria and archaebacteria, suggesting that Oma1 is the founding member of a conserved family of membrane-embedded metallopeptidases, all containing the zinc metalloprotease motif (HEXXH). M48 peptidases proteolytically remove the C-terminal three residues of farnesylated proteins.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 931484038  54 YVTNVGRKIANVCDRRDVKYSFKVLDSEEINAFACPGGYIYIYKGLMKQMDNEAQLAAVLAHEVGHVVARHSAKRIQAvy 133
Cdd:cd07324    1 YLNRLGDRLAAASGRPDLPYRFFVVDDPSINAFALPGGYIFVTTGLLLLLESEDELAAVLAHEIGHVTLRHIARQLER-- 78

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 931484038 134 gysiamevalgdkmsatarqlvdaatglillgYGRENEYEADNYGILYAKNAGYNPKGMIQIFQKFKQMEGKPPSTFEKL 213
Cdd:cd07324   79 --------------------------------YSRDQEREADRLGLQLLARAGYDPRGMARFFERLARQEGLSGSRLPEF 126

                        170
                 ....*....|.
gi 931484038 214 LMSHPPASDRI 224
Cdd:cd07324  127 LSTHPLTAERI 137

Peptidase M48C, integral membrane endopeptidase; This subfamily contains peptidase M48C Oma1 (also called mitochondrial metalloendopeptidase OMA1) protease homologs that are mostly uncharacterized. Oma1 is part of the quality control system in the inner membrane of mitochondria, with its catalytic site facing the matrix space. It cleaves and thereby promotes the turnover of mistranslated or misfolded membrane proteins. Oma1 can cleave the misfolded multi-pass membrane protein Oxa1, thus exerting a function similar to the ATP-dependent m-AAA protease for quality control of inner membrane proteins; it cleaves a misfolded polytopic membrane protein at multiple sites. It has been proposed that in the absence of m-AAA protease, proteolysis of Oxa1 is mediated by Oma1 in an ATP-independent manner. Oma1 is part of highly conserved mitochondrial metallopeptidases, with homologs present in higher eukaryotes, eubacteria and archaebacteria, all containing the zinc binding motif (HEXXH). It forms a high molecular mass complex in the inner membrane, possibly a homo-hexamer.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 931484038  55 VTNVGRKIANVCDR-----RDVKYSFKVLDSEEINAFACPGGYIYIYKGLMKQMDNEAQLAAVLAHEVGHVVARHSAKRI 129
Cdd:cd07331    1 VRRVAARLIAAAGDdppqsAGWDWEVHVIDSPEVNAFVLPGGKIFVFTGLLPVAKNDDELAAVLGHEIAHALARHSAERM 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 931484038 130 ---QAVYGYSIAMEVALGDKMSATARQLVD-AATGLILLGYGRENEYEADNYGILYAKNAGYNPKGMIQIFQKFKQMEG- 204
Cdd:cd07331   81 sqqKLLQLLLLLLLAALGASLAGLALGLLGlGAQLGLLLPYSRKQELEADRIGLQLMAKAGYDPRAAVTFWEKMAAAEGg 160

                        170       180
                 ....*....|....*....|.
gi 931484038 205 -KPPstfeKLLMSHPPASDRI 224
Cdd:cd07331  161 gKPP----EFLSTHPSSETRI 177

Peptidase M48C Ste24p loiP-like, integral membrane protein; This subfamily contains peptidase M48 Ste24p protease loiP (formerly yggG)-like family are mostly uncharacterized proteins that include E. coli loiP and ycaLG, considered to be putative metallopeptidases, containing a zinc-binding motif, HEXXH, and a COOH-terminal ER retrieval signal (KKXX). They proteolytically remove the C-terminal three residues of farnesylated proteins. They are integral membrane proteins associated with the endoplasmic reticulum and golgi, binding one zinc ion per subunit. In eukaryotes, Ste24p is required for the first NH2-terminal proteolytic processing event within the a-factor precursor, which takes place after COOH-terminal CAAX modification (C is cysteine; A is usually aliphatic; X is one of several amino acids) is complete. Mutation studies have shown that the HEXXH protease motif, which is extracellular but adjacent to a transmembrane domain and therefore close to the membrane surface, is critical for Ste24p activity. LoiP has been shown to be a metallopeptidase that cleaves its targets preferentially between Phe-Phe residues. It is upregulated when bacteria are subjected to media of low osmolarity, thus yggG was named LoiP (low osmolarity induced protease). Proper membrane localization of LoiP may depend on YfgC, another putative metalloprotease in this subfamily.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 931484038  75 FKVLDSEEINAFACPGGYIYIYKGLMKQMDNEaQLAAVLAHEVGHVVARHSAKRIQAVYGYSIAMEVAL---GDKMSATA 151
Cdd:cd07334   61 FKVYLTPDVNAFAMADGSVRVYSGLMDMMTDD-ELLGVIGHEIGHVKLGHSKKAMKTAYLTSAARKAAAsasGTVGALSD 139

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 931484038 152 RQLVDAATGLILLGYGRENEYEADNYGILYAKNAGYNPKGMIQIFQKFKQMEGkppSTFEKLLMSHPPASDRI 224
Cdd:cd07334  140 SQLGALAEKLINAQFSQKQESEADDYGYKFLKKNGYNPQAAVSALEKLAALSG---GGKSSLFSSHPDPAKRA 209

M48C peptidase, integral membrane endopeptidase; This subfamily contains peptidase M48C Oma1 (also called mitochondrial metalloendopeptidase OMA1) protease homologs that are mostly uncharacterized. Oma1 is part of the quality control system in the inner membrane of mitochondria, with its catalytic site facing the matrix space. It cleaves and thereby promotes the turnover of mistranslated or misfolded membrane proteins. Oma1 can cleave the misfolded multi-pass membrane protein Oxa1, thus exerting a function similar to the ATP-dependent m-AAA protease for quality control of inner membrane proteins; it cleaves a misfolded polytopic membrane protein at multiple sites. It has been proposed that in the absence of m-AAA protease, proteolysis of Oxa1 is mediated by Oma1 in an ATP-independent manner. Oma1 is part of highly conserved mitochondrial metallopeptidases, with homologs present in higher eukaryotes, eubacteria and archaebacteria, all containing the zinc binding motif (HEXXH). It forms a high molecular mass complex in the inner membrane, possibly a homo-hexamer.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 931484038  73 YSFKVLDSEEINAFAcPGGYIYIYKGLMKQMDNEAQLAAVLAHEVGHVVARHSAKRiqavygysiamevalgdKMSATAR 152
Cdd:cd07342   21 YRVELGNSDGVNAYA-DGRRVQITSGMMDFAQDDDELALVVAHELAHNILGHRDRL-----------------RANGVAG 82

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 931484038 153 QLVDAatGLILLGYGRENEYEADNYGILYAKNAGYNPKGMIQIFQKFKQMegKPPSTFekLLMSHPPASDRI 224
Cdd:cd07342   83 GLLDG--FGGNAAYSREFEIEADYLGLYLMARAGYDIDGAADFWRRLGAS--HPVGIG--RAATHPSTAERF 148

M48 Ste24 endopeptidase-like, integral membrane metallopeptidase; This family contains peptidase M48 family Ste24p-like proteins that are as yet uncharacterized, but probably function as intracellular, membrane-associated zinc metalloproteases; they all contain the HEXXH Zn-binding motif, which is critical for Ste24p activity. They likely remove the C-terminal three residues of farnesylated proteins proteolytically and are possibly associated with the endoplasmic reticulum and golgi. Some members also contain ankyrin domains which occur in very diverse families of proteins and mediate protein-protein interactions.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 931484038  77 VLDSEEINAFA-CPGG--YIYIYKGLMKQMDnEAQLAAVLAHEVGHVVARHSAKRIQAVYGYSIAMEVALGdkmsatarq 153
Cdd:cd07325   36 VYQSPVLNAFAlGFEGrpFIVLNSGLVELLD-DDELRFVIGHELGHIKSGHVLYRTLLLLLLLLGELIGIL--------- 105

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 931484038 154 LVDAATGLILLGYGRENEYEADNYGILYAKN-----------AGYNPKG----MIQIFQKFKQMEGKPPSTF---EKLLM 215
Cdd:cd07325  106 LLSSALPLALLAWSRAAEYSADRAGLLVCQDpeaairalmklAGGSKLLkdvnNIEYFLEEEAQADALDGFFkwlSELLS 185

                 ....*....
gi 931484038 216 SHPPASDRI 224
Cdd:cd07325  186 THPFLVKRA 194

Peptidase M48 subfamily A, a type 1 CaaX endopeptidase; This family contains peptidase family M48 subfamily A which includes a number of well-characterized genes such as those found in humans (ZMPSTE24, also known as farnesylated protein-converting enzyme 1 or FACE-1 or Hs Ste24), Taenia solium metacestode (TsSte24p), Arabidopsis (AtSte24) and yeast (Ste24p). Ste24p contains the zinc metalloprotease motif (HEXXH), likely exposed on the cytoplasmic side. It is thought to be intimately associated with the endoplasmic reticulum (ER), regardless of whether its genes possess the conventional signal motif (KKXX) in the C-terminal. Proteins in this family proteolytically remove the C-terminal three residues of farnesylated proteins. Ste24p is involved in the post-translational processing of prelamin A to mature lamin A, a major component of the nuclear envelope. ZmpSte24 deficiency causes an accumulation of prelamin A leading to lipodystrophy and other disease phenotypes, while mutations in this gene or in that encoding its substrate, prelamin A, result in a series of human inherited diseases known as laminopathies, the most severe of which are Hutchinson Gilford progeria syndrome (HGPS) and restrictive dermopathy (RD) which arise due to unsuccessful maturation of prelamin A. Two forms of mandibuloacral dysplasia, a condition that causes a variety of abnormalities involving bone development, skin pigmentation, and fat distribution, are caused by mutations in two different genes; mutations in the LMNA gene, which normally provides instructions for making lamin A and lamin C, cause mandibuloacral dysplasia with A-type lipodystrophy (MAD-A), and mutations in the ZMPSTE24 gene cause mandibuloacral dysplasia with B-type lipodystrophy (MAD-B). Within cells, these genes are involved in maintaining the structure of the nucleus and may play a role in many cellular processes. Certain HIV protease inhibitors have been shown to inhibit the enzymatic activity of ZMPSTE24, but not enzymes involved in prelamin A processing.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 931484038  93 IYIYKGLMKQMDNEaQLAAVLAHEVGHVVARHSAKRI---QA-----VYGYSIAMEVAL------GDKMSATAR------ 152
Cdd:cd07343  250 IVLFDTLLEQLTED-EILAVLAHELGHWKHGHILKGLilsQLllflgFYLFGLLLNNPSlyrafgFFGPSDQPAligfll 328

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 931484038 153 --QLVDAATGLILLGYGRENEYEADNygilYAKNAGYNpKGMIQIFQKFkQMEGK----PPSTFEKLLMSHPPASDRI 224
Cdd:cd07343  329 llSPLSFLLSPLMNALSRKFEYEADA----FAVELGYG-EALISALVKL-SKDNLsnltPDPLYSAFHYSHPPLLERI 400

Peptidase M48 subfamily B HtpX-like membrane-bound metallopeptidase; This HtpX family of peptidase M48 subfamily B includes uncharacterized HtpX homologs and consists of proteins smaller than Ste24p, with homology restricted to the C-terminal half of Ste24p. HtpX expression is controlled by the Cpx stress response system, which senses abnormal membrane proteins. HtpX participates in the proteolytic quality control of these misfolded proteins by undergoing self-degradation and collaborating with FtsH, a membrane-bound and ATP-dependent protease, to eliminate them. HtpX, a zinc metalloprotease with an active site motif HEXXH, has an FtsH-like topology, and is capable of introducing endoproteolytic cleavages into SecY (also an FtsH substrate). However, HtpX does not have an ATPase activity and will only act against cytoplasmic regions of a target membrane protein. Thus, HtpX and FtsH have overlapping and/or complementary functions, which are especially important at high temperature; in E. coli and Xylella fastidiosa, HtpX is heat-inducible, while in Streptococcus gordonii it is not.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 931484038  77 VLDSEEINAFACpgGY------IYIYKGLMKQMDNEaQLAAVLAHEVGHVV---ARHSAKRIQAVYGYSIAMEVAL--GD 145
Cdd:cd07340   51 IIDDPAPNAFAT--GRnpehavIAVTTGLLEKLNRD-ELEGVIAHELSHIKnydIRLMTIAVVLVGIIALIADLALrsFF 127

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 931484038 146 KMSATAR---------QLVDAATGLILLGYG------------RENEYEADNYGILYAKnagyNPKGMIQIFQKFKQ--- 201
Cdd:cd07340  128 YGGGSRRrrrdgggggALILLILGLVLIILApifaqliqlaisRQREYLADASAVELTR----NPEGLISALEKISGdss 203

                        170       180       190
                 ....*....|....*....|....*....|....*....
gi 931484038 202 ----------------MEGKPPSTFEKLLMSHPPASDRI 224
Cdd:cd07340  204 plkvansatahlnlyfPNPGKKSSFSSLFSTHPPIEERI 242

Peptidases M48 (Ste24 endopeptidase or htpX homolog) and M56 (in MecR1 and BlaR1), integral membrane metallopeptidases; This family contains peptidase M48 (also known as Ste24 peptidase, Ste24p, Ste24 endopeptidase, a-factor converting enzyme, AFC1), M56 (also known as BlaR1 peptidase) as well as a novel family called minigluzincins. Peptidase M48 belongs to Ste24 endopeptidase family. Members of this family include Ste24 protease (peptidase M48A), protease htpX homolog (peptidase M48B), or CAAX prenyl protease 1, and mitochondrial metalloendopeptidase OMA1 (peptidase M48C). They proteolytically remove the C-terminal three residues of farnesylated proteins. They are integral membrane proteins associated with the endoplasmic reticulum and golgi, binding one zinc ion per subunit. In eukaryotes, Ste24p is required for the first NH2-terminal proteolytic processing event within the a-factor precursor, which takes place after COOH-terminal CAAX modification (C is cysteine; A is usually aliphatic; X is one of several amino acids) is complete. The Ste24p contains multiple membrane spans, a zinc metalloprotease motif (HEXXH), and a COOH-terminal ER retrieval signal (KKXX). Mutation studies have shown that the HEXXH protease motif, which is extracellular but adjacent to a transmembrane domain and therefore close to the membrane surface, is critical for Ste24p activity. Ste24p has limited homology to HtpX family of prokaryotic proteins; HtpX proteins, also part of the M48 peptidase family, are smaller and homology is restricted to the C-terminal half of Ste24p. HtpX expression is controlled by the Cpx stress response system, which senses abnormal membrane proteins; HtpX then undergoes self-degradation and collaborates with FtsH to eliminate these misfolded proteins. Peptidase M56 includes zinc metalloprotease domain in MecR1 and BlaR1. MecR1 is a transmembrane beta-lactam sensor/signal transducer protein that regulates the expression of an altered penicillin-binding protein PBP2a, which resists inactivation by beta-lactam antibiotics, in methicillin-resistant Staphylococcus aureus (MRSA). BlaR1 regulates the inducible expression of a class A beta-lactamase that hydrolytically destroys certain beta-lactam antibiotics in MRSA. Also included are a novel family of related proteins that consist of the soluble minimal scaffold similar to the catalytic domains of the integral-membrane metallopeptidase M48 and M56, thus called minigluzincins.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....
gi 931484038  72 KYSFKVLDSEEINAFACPG--GYIYIYKGLMKQMdNEAQLAAVLAHEVGHVVAR 123
Cdd:cd05843   17 LDKVVVVPGSVPNAFFTGGanKRVVLTTALLELL-SEEELAAVIAHELGHFKAH 69

Peptidase M56-like including those in BlaR1 and MecR1, integral membrane metallopeptidase; This family contains peptidase M56, which includes zinc metalloprotease domain in MecR1 as well as BlaR1. MecR1 is a transmembrane beta-lactam sensor/signal transducer protein that regulates the expression of an altered penicillin-binding protein PBP2a, which resists inactivation by beta-lactam antibiotics, in methicillin-resistant Staphylococcus aureus (MRSA). BlaR1 regulates the inducible expression of a class A beta-lactamase that hydrolytically destroys certain ?-lactam antibiotics in MRSA. Both, MecR1 and BlaR1, are transmembrane proteins that consist of four transmembrane helices, a cytoplasmic zinc protease domain, and the soluble C-terminal extracellular sensor domain, and are highly similar in sequence and function. The signal for protein expression is transmitted by site-specific proteolytic cleavage of both the transducer, which auto-activates, and the repressor, which is inactivated, unblocking gene transcription. All members contain the zinc metalloprotease motif (HEXXH). Homologs of this peptidase domain are also found in a number of other bacterial genome sequences, most of which are as yet uncharacterized.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|
gi 931484038  77 VLDSEEINAFACPG--GYIYIYKGLMKQMDnEAQLAAVLAHEVGHVVARH 124
Cdd:cd07326   31 VVDHDAPLAFCLGGrrPRIVLSTGLLELLS-PEELRAVLAHERAHLRRRD 79

Peptidase M48 subfamily B HtpX-like membrane-bound metallopeptidase; This HtpX family of peptidase M48 subfamily B includes uncharacterized HtpX homologs and consists of proteins smaller than Ste24p, with homology restricted to the C-terminal half of Ste24p. HtpX expression is controlled by the Cpx stress response system, which senses abnormal membrane proteins. HtpX participates in the proteolytic quality control of these misfolded proteins by undergoing self-degradation and collaborating with FtsH, a membrane-bound and ATP-dependent protease, to eliminate them. HtpX, a zinc metalloprotease with an active site motif HEXXH, has an FtsH-like topology, and is capable of introducing endoproteolytic cleavages into SecY (also an FtsH substrate). However, HtpX does not have an ATPase activity and will only act against cytoplasmic regions of a target membrane protein. Thus, HtpX and FtsH have overlapping and/or complementary functions, which are especially important at high temperature; in E. coli and Xylella fastidiosa, HtpX is heat-inducible, while in Streptococcus gordonii it is not.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 931484038  84 NAFA----CPGGYIYIYKGLMKQMdNEAQLAAVLAHEVGHVVARHSAKrIQAV--------YGYSIAMEVALGDKMSATA 151
Cdd:cd07338   62 NAFAygspLTGARVAVTRGLLDIL-NRDELEAVIGHELGHIKHRDVAI-MTAIglipsiiyYIGRSLLFSGGSSGGRNGG 139

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 931484038 152 RQLVDAA---------TGLILLGYGRENEYEADNYGilyAKNAGyNPKGM------IQIFqkfkqmegkppsTFEKLLMS 216
Cdd:cd07338  140 GALLAVGiaafavyflFQLLVLGFSRLREYYADAHS---AKVTG-NGRALqsalakIAYG------------YLAEIFST 203

                 ....*...
gi 931484038 217 HPPASDRI 224
Cdd:cd07338  204 HPLPAKRI 211

heat shock protein HtpX; Provisional

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....
gi 931484038  77 VLDSEEINAFAcpGGY------IYIYKGLMKQMDnEAQLAAVLAHEVGHVvaRH 124
Cdd:PRK02870 138 IIDAPYMNAFA--SGYseksamVAITTGLLEKLD-RDELQAVMAHELSHI--RH 186