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 18405231 116 IGTSVLVSKNQLSDLHGLLVEAAEILNIEA-PDLYVRQSPVPNAYTLAISGKkPFIVVHTSLIELLTSAELQAVLAHELG 194
Cdd:cd07325   1 LGNSVRVTPRQFPELHALLVEACRILGLKKvPELYVYQSPVLNAFALGFEGR-PFIVLNSGLVELLDDDELRFVIGHELG 79

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18405231 195 HLKCDHGVWLTFANILTLGAYTVPAFgqMIARTLEEQLLRWLRSAELTCDRAALLVAQDPKVVVSVLMKLAGGCPSIADQ 274
Cdd:cd07325  80 HIKSGHVLYRTLLLLLLLLGELIGIL--LLSSALPLALLAWSRAAEYSADRAGLLVCQDPEAAIRALMKLAGGSKLLKDV 157

                       170       180       190       200
                ....*....|....*....|....*....|....*....|....*..
gi 18405231 275 LNVDAFLEQARSYDkasssPLGWYIRNAQTSQLSHPLPVLRAREIDE 321
Cdd:cd07325 158 NNIEYFLEEEAQAD-----ALDGFFKWLSELLSTHPFLVKRAAELLR 199

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 18405231 116 IGTSVLVSKNQLSDLHGLLVEAAEILNIEA-PDLYVRQSPVPNAYTLAISGKkPFIVVHTSLIELLTSAELQAVLAHELG 194
Cdd:cd07325   1 LGNSVRVTPRQFPELHALLVEACRILGLKKvPELYVYQSPVLNAFALGFEGR-PFIVLNSGLVELLDDDELRFVIGHELG 79

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18405231 195 HLKCDHGVWLTFANILTLGAYTVPAFgqMIARTLEEQLLRWLRSAELTCDRAALLVAQDPKVVVSVLMKLAGGCPSIADQ 274
Cdd:cd07325  80 HIKSGHVLYRTLLLLLLLLGELIGIL--LLSSALPLALLAWSRAAEYSADRAGLLVCQDPEAAIRALMKLAGGSKLLKDV 157

                       170       180       190       200
                ....*....|....*....|....*....|....*....|....*..
gi 18405231 275 LNVDAFLEQARSYDkasssPLGWYIRNAQTSQLSHPLPVLRAREIDE 321
Cdd:cd07325 158 NNIEYFLEEEAQAD-----ALDGFFKWLSELLSTHPFLVKRAAELLR 199

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 18405231   129 DLHGLLVEAAEILNIEAPDLY---VRQSPVPNAYTlaiSGKKP--FIVVHTSLIELLTS-AELQAVLAHELGHLKCDHGV 202
Cdd:pfam01435   6 ELQRVVERLAAAAGLPLPPWYvvvIKSSPVPNAFA---YGLLPggRVVVTTGLLDLLETeDELAAVLGHEIGHIKARHSV 82

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18405231   203 ----------WLTFANILTLG---AYTVPAFGQMIARTLE------EQLLRWL-RSAELTCDRAALLVAQDPKVVVSVLM 262
Cdd:pfam01435  83 eslsimgglsLAQLFLALLLLgaaASGFANFGIIFLLLIGplaallTLLLLPYsRAQEYEADRLGAELMARAGYDPRALI 162

                         170       180       190       200       210       220
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 18405231   263 KLAGgcpsiadqlnvdafleqarsYDKASSSPLGWYIRNAQTSqlSHPLPVLRAREIDEW 322
Cdd:pfam01435 163 KLWG--------------------EIDNNGRASDGALYPELLS--THPSLVERIAALRER 200

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 18405231 116 IGTSVLVSKNQLSDLHGLLVEAAEILNIEA-PDLYVRQSPVPNAYTLAISGKkPFIVVHTSLIELLTSAELQAVLAHELG 194
Cdd:cd07325   1 LGNSVRVTPRQFPELHALLVEACRILGLKKvPELYVYQSPVLNAFALGFEGR-PFIVLNSGLVELLDDDELRFVIGHELG 79

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18405231 195 HLKCDHGVWLTFANILTLGAYTVPAFgqMIARTLEEQLLRWLRSAELTCDRAALLVAQDPKVVVSVLMKLAGGCPSIADQ 274
Cdd:cd07325  80 HIKSGHVLYRTLLLLLLLLGELIGIL--LLSSALPLALLAWSRAAEYSADRAGLLVCQDPEAAIRALMKLAGGSKLLKDV 157

                       170       180       190       200
                ....*....|....*....|....*....|....*....|....*..
gi 18405231 275 LNVDAFLEQARSYDkasssPLGWYIRNAQTSQLSHPLPVLRAREIDE 321
Cdd:cd07325 158 NNIEYFLEEEAQAD-----ALDGFFKWLSELLSTHPFLVKRAAELLR 199

Peptidase M56-like, integral membrane metallopeptidase in bacteria; 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 beta-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        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18405231 136 EAAEILNIEAPDLYVRQSPVPNAYTLAISGKkPFIVVHTSLIELLTSAELQAVLAHELGHLKCDH----GVWLTFANILT 211
Cdd:cd07329   2 RLARQADVPPPRVYVVDSDVPNAFAVGRSRG-PTVVVTTGLLDLLDDDELEAVLAHELAHLKRRDvlvlLLFDPLLLLVV 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18405231 212 LGAYTVPAFGQMIARTLEEQLLRWLRS-----AELTCD----------RAALLVAqDPKVVVSVLMKLAGGCPSIADQLN 276
Cdd:cd07329  81 GLLLFLSLFIFELLGFFFQPLLFLAFFallrlAELLADalavartsaaRRARLTG-LPAALASALEKIEDASDRALEAGL 159

                       170
                ....*....|....*...
gi 18405231 277 VDAFLEQARSYDKASSSP 294
Cdd:cd07329 160 VLPALAADASSLEKTDHP 177

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 18405231   129 DLHGLLVEAAEILNIEAPDLY---VRQSPVPNAYTlaiSGKKP--FIVVHTSLIELLTS-AELQAVLAHELGHLKCDHGV 202
Cdd:pfam01435   6 ELQRVVERLAAAAGLPLPPWYvvvIKSSPVPNAFA---YGLLPggRVVVTTGLLDLLETeDELAAVLGHEIGHIKARHSV 82

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18405231   203 ----------WLTFANILTLG---AYTVPAFGQMIARTLE------EQLLRWL-RSAELTCDRAALLVAQDPKVVVSVLM 262
Cdd:pfam01435  83 eslsimgglsLAQLFLALLLLgaaASGFANFGIIFLLLIGplaallTLLLLPYsRAQEYEADRLGAELMARAGYDPRALI 162

                         170       180       190       200       210       220
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 18405231   263 KLAGgcpsiadqlnvdafleqarsYDKASSSPLGWYIRNAQTSqlSHPLPVLRAREIDEW 322
Cdd:pfam01435 163 KLWG--------------------EIDNNGRASDGALYPELLS--THPSLVERIAALRER 200

heat shock protein HtpX; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18405231  122 VSKNQLSDLHGLLVEAAEILNIEAPDLYVRQSPVPNAYTLAISGKKPFIVVHTSLIELLTSAELQAVLAHELGHLKCDHG 201
Cdd:PRK02391  70 VSEDEYPELHAMVERLCALADLPKPRVAVADSDVPNAFATGRSPKNAVVCVTTGLMRRLDPDELEAVLAHELSHVKNRDV 149

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18405231  202 VWLTFANILTLGAYTVPAFGQMIA--------RTLEEQLLRWLRSA-----------------ELTCDRAALLVAQDPKV 256
Cdd:PRK02391 150 AVMTIASFLSTIAFLIVRWGFYFGgfggrgggGGGGGILVVILVSLvvwaisflliralsryrEFAADRGAAIITGRPSA 229

                        170
                 ....*....|
gi 18405231  257 VVSVLMKLAG 266
Cdd:PRK02391 230 LASALMKISG 239

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 18405231 122 VSKNQLSDLHGLLVEAAEILNIEAPDLYVRQSPVPNAYTLAISGKKPFIVVHTSLIELLTSAELQAVLAHELGHLK 197
Cdd:cd07338  27 PPDPEYPWLQEIVEEVARRAGIKPPKVGIAEDPIPNAFAYGSPLTGARVAVTRGLLDILNRDELEAVIGHELGHIK 102

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 18405231 122 VSKNQLSDLHGLLVEAAEILNIEAPDLYVRQSPVPNAYTlaiSGKKP---FIVVHTSLIELLTSAELQAVLAHELGHLK 197
Cdd:cd07336  49 VSEEEAPELYQIVEELARRAGLPMPKVYIIPSPQPNAFA---TGRNPehaAVAVTTGILRLLDKDELEGVLAHELAHIK 124

Peptidase M48C Ste24p, 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
                ....*....|....*....|....*....|....*....|....*....|....*....
gi 18405231 146 PDLYVRQSP-VPNAYTLAiSGKkpfIVVHTSLIELLTSA-ELQAVLAHELGHLKCDHGV 202
Cdd:cd07332  67 YRLHFRDSGiGANAFALP-GGT---IVVTDGLVELAESPeELAAVLAHEIGHVEHRHSL 121

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
                ....*....|....*....|....*....|....*....|....*....|..
gi 18405231 146 PDLYVRQSPVPNAYTLAISGKKPFIVVHTSLIELLTSAELQAVLAHELGHLK 197
Cdd:cd07340  47 PKVYIIDDPAPNAFATGRNPEHAVIAVTTGLLEKLNRDELEGVIAHELSHIK 98

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 18405231 147 DLYVRQSPVPNAYTLAiSGKkpfIVVHTSLIELLTS-AELQAVLAHELGHLKCDHGV-WLTFANILTLGAYTVPAFGQMI 224
Cdd:cd07331  25 EVHVIDSPEVNAFVLP-GGK---IFVFTGLLPVAKNdDELAAVLGHEIAHALARHSAeRMSQQKLLQLLLLLLLAALGAS 100

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*
gi 18405231 225 ARTLEEQLLRWL----------RSAELTCDRAAL-LVAQ---DPKVVVSVLMKLA 265
Cdd:cd07331 101 LAGLALGLLGLGaqlglllpysRKQELEADRIGLqLMAKagyDPRAAVTFWEKMA 155

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 18405231 119 SVLVSKNQLSDLHGLLVEAAEILNIEA-PDLYVRQSPVPNAYTLAiSGKKPFIVVHTSLIELLTSAELQAVLAHELGHLK 197
Cdd:cd07339  19 ARPLSPGDAPELYRLLQELARRAGLPRpPLLYYVPSRVLNAFAVG-SRKDAAIALTDGLLRRLTLRELAGVLAHEVSHIR 97

                        90       100
                ....*....|....*....|....*...
gi 18405231 198 CDHGVWLTFANILTLGAYTVPAFGQMIA 225
Cdd:cd07339  98 NGDLRVMGLADLISRLTSLLSLLGQLLL 125

Peptidase M48 CaaX prenyl protease type 1, an integral membrane, Zn-dependent protein; This family of M48 CaaX prenyl protease 1-like family includes a number of well characterized genes such as those found in Taenia solium metacestode (TsSte24p), Arabidopsis (AtSte24), yeast Ste24p and human (Hs Ste24p) as well as several uncharacterized genes such as YhfN, some of which also containing tetratricopeptide (TPR) repeats. All members of this family contain the zinc metalloprotease motif (HEXXH), likely exposed on the cytoplasmic side. They are thought to be intimately associated with the endoplasmic reticulum (ER), regardless of whether their 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. The gene ZmpSte24, also known as FACE-1 in humans, a member of this family, 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 the protein lead to diseases of lamin processing (laminopathies), such as premature aging disease progeria and metabolic disorders. Some of these mutations map to the peptide-binding site.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 18405231 147 DLYVRQSPVPNAYTLAISGKKPFIVVHTSLIELLTSAELQAVLAHELGHLKCDHGVWLTFAN 208
Cdd:cd07330 139 ELSGGSMIHANAYFPGSGKRRRVVVFADALVSLMTPDELLAVIAHELGHVKHHHHLFRLAAS 200

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 18405231 144 EAPDLYVRQSPVPNAYtlAISGKKPFIVVHTSLIELLTSAELQAVLAHELGHLK 197
Cdd:cd05843  16 PLDKVVVVPGSVPNAF--FTGGANKRVVLTTALLELLSEEELAAVIAHELGHFK 67

zinc metalloprotease HtpX;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18405231  120 VLVSKNQLSDLHGLLVEAAEILNIEAPDLYVRQSPVPNAYTlaiSGKKP---FIVVHTSLIELLTSAELQAVLAHELGHL 196
Cdd:PRK03001  59 QEVDENTAPQFYRMVRELAQRAGLPMPKVYLINEDQPNAFA---TGRNPehaAVAATTGILRVLSEREIRGVMAHELAHV 135

                 .
gi 18405231  197 K 197
Cdd:PRK03001 136 K 136

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.

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gi 18405231 176 LIELLTSAELQAVLAHELGHLKCDHGVWLTFANILTLGAY 215
Cdd:cd07343 256 LLEQLTEDEILAVLAHELGHWKHGHILKGLILSQLLLFLG 295

Peptidase M48 subfamily A-like, putative CaaX prenyl protease; This family contains peptidase family M48 subfamily A-like CaaX prenyl protease 1, most of which are uncharacterized. Some of these contain tetratricopeptide (TPR) repeats at the C-terminus. Proteins in this family contain the zinc metalloprotease motif (HEXXH), likely exposed on the cytoplasmic side. They are thought to be possibly associated with the endoplasmic reticulum (ER), regardless of whether their genes possess the conventional signal motif (KKXX) in the C-terminal. These proteins putatively remove the C-terminal three residues of farnesylated proteins proteolytically.

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gi 18405231 128 SDLHGLLVEAAEILNIEAPDLYV---RQSPVPNAYTLAISGKKPFIVVHTSLIELLTSAELQAVLAHELGHLK 197
Cdd:cd07345 145 GPLRDRLEAFCRRAGFKVADILVwplFEGRVATAGVMGILPRFRYILITDALLDSLSPEELEAVLAHEIGHVK 217

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.

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gi 18405231 167 KPFIVVHTSLIELlTSAELQAVLAHELGHLK-CDHgvwltFANILTLGAYTV----PAFGQMIARtleeqlLRWLRsaEL 241
Cdd:cd07341  66 RPVILLPEGLLEG-SPEELRAILLHELAHIRrRDL-----LVNLLQRLLEALfwfnPLVWLLSRR------LRLER--EL 131

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gi 18405231 242 TCDRAALLVAQDPKVVVSVLMKLAGGCPSIADQLNV 277
Cdd:cd07341 132 ACDEAVLAALGDKEDYAEALLRLAERRSQPPPALAL 167