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        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 45551547  42 HILCLVIVVHNSFHLILCCRQLKLCKRTSVPPKQMEGILSQEAFQASKDKQLHASSLEIFNIAIDTLYSCLDLYLCTLAF 121
Cdd:cd07343   1 YIILLLLVLVYLFELYLSLRQLRHLKRKLPPPPELADVISQEEFEKAQAYSLDKSRFSIVSSLLSLLLLLLLLLFGLLPL 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 45551547 122 LWKLTVGWYHYadSTWLNVTFMTVFSTYLVVRKLPSLFYEKLVLDPRY--NvdpeKTPP-----------LLGLIcalvf 188
Cdd:cd07343  81 LDLLLRSLGGN--EILQSLLFFLLLSLISTLLSLPFSLYSTFVIEEKFgfN----KQTLglfikdllkslLLSLV----- 149

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 45551547 189 vvvflqvAVIPLTAIFMAIHMLSEWYFTLFVWLGLVGLSVLVLAFVGLFGVPCLGKSRKMNSTDMDNSLKAVLDDFNFP- 267
Cdd:cd07343 150 -------LGGPLLALLLWIIKKFGKYWWLYAWLFVVVFSLLLMFIYPTLIAPLFNKFTPLEDGELKTKIEALAKRAGFPl 222

                       250       260       270       280       290       300       310       320
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 45551547 268 GRVYMV-------HTfhvgrpTAWVMGCCCCLRLDIHDNLKwnrgfssddfdwgqmgAGLNDEQLAAFVAHQLAHWQLWH 340
Cdd:cd07343 223 KKVYVMdgskrstHS------NAYFTGFGKNKRIVLFDTLL----------------EQLTEDEILAVLAHELGHWKHGH 280

                       330       340       350       360       370       380       390       400
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 45551547 341 VAKGLALIYFYLLIYLLLFGICNRWITLYAAAGFT--TFYPSSVGFWLVYkylmPIYHDISTWIVFFCIRHFEYAADAYV 418
Cdd:cd07343 281 ILKGLILSQLLLFLGFYLFGLLLNNPSLYRAFGFFgpSDQPALIGFLLLL----SPLSFLLSPLMNALSRKFEYEADAFA 356

                       410       420       430       440
                ....*....|....*....|....*....|....*....|....*....
gi 45551547 419 NRRGYGLPMRAALLKLFSDDYEFPYVDQCYLMWHRLRPSVLQRIDNLQR 467
Cdd:cd07343 357 VELGYGEALISALVKLSKDNLSNLTPDPLYSAFHYSHPPLLERIAALEK 405

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 45551547  42 HILCLVIVVHNSFHLILCCRQLKLCKRTSVPPKQMEGILSQEAFQASKDKQLHASSLEIFNIAIDTLYSCLDLYLCTLAF 121
Cdd:cd07343   1 YIILLLLVLVYLFELYLSLRQLRHLKRKLPPPPELADVISQEEFEKAQAYSLDKSRFSIVSSLLSLLLLLLLLLFGLLPL 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 45551547 122 LWKLTVGWYHYadSTWLNVTFMTVFSTYLVVRKLPSLFYEKLVLDPRY--NvdpeKTPP-----------LLGLIcalvf 188
Cdd:cd07343  81 LDLLLRSLGGN--EILQSLLFFLLLSLISTLLSLPFSLYSTFVIEEKFgfN----KQTLglfikdllkslLLSLV----- 149

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 45551547 189 vvvflqvAVIPLTAIFMAIHMLSEWYFTLFVWLGLVGLSVLVLAFVGLFGVPCLGKSRKMNSTDMDNSLKAVLDDFNFP- 267
Cdd:cd07343 150 -------LGGPLLALLLWIIKKFGKYWWLYAWLFVVVFSLLLMFIYPTLIAPLFNKFTPLEDGELKTKIEALAKRAGFPl 222

                       250       260       270       280       290       300       310       320
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 45551547 268 GRVYMV-------HTfhvgrpTAWVMGCCCCLRLDIHDNLKwnrgfssddfdwgqmgAGLNDEQLAAFVAHQLAHWQLWH 340
Cdd:cd07343 223 KKVYVMdgskrstHS------NAYFTGFGKNKRIVLFDTLL----------------EQLTEDEILAVLAHELGHWKHGH 280

                       330       340       350       360       370       380       390       400
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 45551547 341 VAKGLALIYFYLLIYLLLFGICNRWITLYAAAGFT--TFYPSSVGFWLVYkylmPIYHDISTWIVFFCIRHFEYAADAYV 418
Cdd:cd07343 281 ILKGLILSQLLLFLGFYLFGLLLNNPSLYRAFGFFgpSDQPALIGFLLLL----SPLSFLLSPLMNALSRKFEYEADAFA 356

                       410       420       430       440
                ....*....|....*....|....*....|....*....|....*....
gi 45551547 419 NRRGYGLPMRAALLKLFSDDYEFPYVDQCYLMWHRLRPSVLQRIDNLQR 467
Cdd:cd07343 357 VELGYGEALISALVKLSKDNLSNLTPDPLYSAFHYSHPPLLERIAALEK 405

Zn-dependent protease with chaperone function [Posttranslational modification, protein turnover, chaperones];

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 45551547 320 LNDEQLAAFVAHQLAHWQLWHVAKGLAliyfylliyllLFGICNRWITLYAAAGFTTFYPSSVGFW--LVYKYLMPIyhd 397
Cdd:COG0501  54 LDRDELEAVLAHELGHIKNGDILLMTL-----------ASGLLGLIGFLARLLPLAFGRDRDAGLLlgLLLGILAPF--- 119

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 45551547 398 ISTWIVFFCIRHFEYAADAY-VNRRGYGLPMRAALLKLFSDDYEFPYVDQCYLMWHRLR-------------PSVLQRID 463
Cdd:COG0501 120 LATLIQLALSRKREYEADRAaAELTGDPDALASALRKLAGGNLSIPLRRAFPAQAHAFIinplklsslfsthPPLEERIA 199

                ....*
gi 45551547 464 NLQRL 468
Cdd:COG0501 200 RLREL 204

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 45551547  42 HILCLVIVVHNSFHLILCCRQLKLCKRTSVPPKQMEGILSQEAFQASKDKQLHASSLEIFNIAIDTLYSCLDLYLCTLAF 121
Cdd:cd07343   1 YIILLLLVLVYLFELYLSLRQLRHLKRKLPPPPELADVISQEEFEKAQAYSLDKSRFSIVSSLLSLLLLLLLLLFGLLPL 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 45551547 122 LWKLTVGWYHYadSTWLNVTFMTVFSTYLVVRKLPSLFYEKLVLDPRY--NvdpeKTPP-----------LLGLIcalvf 188
Cdd:cd07343  81 LDLLLRSLGGN--EILQSLLFFLLLSLISTLLSLPFSLYSTFVIEEKFgfN----KQTLglfikdllkslLLSLV----- 149

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 45551547 189 vvvflqvAVIPLTAIFMAIHMLSEWYFTLFVWLGLVGLSVLVLAFVGLFGVPCLGKSRKMNSTDMDNSLKAVLDDFNFP- 267
Cdd:cd07343 150 -------LGGPLLALLLWIIKKFGKYWWLYAWLFVVVFSLLLMFIYPTLIAPLFNKFTPLEDGELKTKIEALAKRAGFPl 222

                       250       260       270       280       290       300       310       320
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 45551547 268 GRVYMV-------HTfhvgrpTAWVMGCCCCLRLDIHDNLKwnrgfssddfdwgqmgAGLNDEQLAAFVAHQLAHWQLWH 340
Cdd:cd07343 223 KKVYVMdgskrstHS------NAYFTGFGKNKRIVLFDTLL----------------EQLTEDEILAVLAHELGHWKHGH 280

                       330       340       350       360       370       380       390       400
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 45551547 341 VAKGLALIYFYLLIYLLLFGICNRWITLYAAAGFT--TFYPSSVGFWLVYkylmPIYHDISTWIVFFCIRHFEYAADAYV 418
Cdd:cd07343 281 ILKGLILSQLLLFLGFYLFGLLLNNPSLYRAFGFFgpSDQPALIGFLLLL----SPLSFLLSPLMNALSRKFEYEADAFA 356

                       410       420       430       440
                ....*....|....*....|....*....|....*....|....*....
gi 45551547 419 NRRGYGLPMRAALLKLFSDDYEFPYVDQCYLMWHRLRPSVLQRIDNLQR 467
Cdd:cd07343 357 VELGYGEALISALVKLSKDNLSNLTPDPLYSAFHYSHPPLLERIAALEK 405

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        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 45551547 323 EQLAAFVAHQLAHWQLWHVAKGLAliyfylliylllfgicnrwitLYAAAGFTTFYpssvgfwlvykyLMPIYHDISTWI 402
Cdd:cd07330 175 DELLAVIAHELGHVKHHHHLFRLA---------------------ASQAVSFIVCA------------LFILIYPLRFLL 221

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 45551547 403 VFFcIRHFEYAADAYVNRRGYGLPMRAALLKLFSDDYEFPYVDQCYLMWHRLRPSVLQRIDNLQR 467
Cdd:cd07330 222 NFF-ARRFEYQADAYAAKLAGADALISALVKLHRDNLTTLTPSRLYSLWHYSHPHAAMRVAHLLR 285

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 45551547   321 NDEQLAAFVAHQLAHWQLWHVAKGLALIYFYLLIYLLLFGICNRWitlyAAAGFTTFYPSSVGFWLVYKYLMpiyhdisT 400
Cdd:pfam01435  61 TEDELAAVLGHEIGHIKARHSVESLSIMGGLSLAQLFLALLLLGA----AASGFANFGIIFLLLIGPLAALL-------T 129

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 45551547   401 WIVFFCIRHFEYAADA----YVNRRGYglpMRAALLKLF--SDDYEFPYVDQCYLMWHRLRPSVLQRIDNLQRL 468
Cdd:pfam01435 130 LLLLPYSRAQEYEADRlgaeLMARAGY---DPRALIKLWgeIDNNGRASDGALYPELLSTHPSLVERIAALRER 200

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 45551547 320 LNDEQLAAFVAHQLAHWQLWHVAKGLALIYFYlliylllfgicnRWITLYAAAGFTTFYPSSVGFwlvykylmpiYHDIS 399
Cdd:cd07329  45 LDDDELEAVLAHELAHLKRRDVLVLLLFDPLL------------LLVVGLLLFLSLFIFELLGFF----------FQPLL 102

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 45551547 400 TWIVFFCIRHFEYAADAYVNRR----------GYGLPMRAALLKLFSDDYEFPYVDQCYL--------MWHRLRPSVLQR 461
Cdd:cd07329 103 FLAFFALLRLAELLADALAVARtsaarrarltGLPAALASALEKIEDASDRALEAGLVLPalaadassLEKTDHPPLEER 182

                ....*.
gi 45551547 462 IDNLQR 467
Cdd:cd07329 183 VERLLE 188