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Conserved domains on  [gi|90403592|ref|NP_000435.3|]
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phosphate-regulating neutral endopeptidase isoform 1

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List of domain hits

Name Accession Description Interval E-value
M13 cd08662
Peptidase family M13 includes neprilysin, endothelin-converting enzyme I; M13 family of ...
74-747 0e+00

Peptidase family M13 includes neprilysin, endothelin-converting enzyme I; M13 family of metallopeptidases includes neprilysin (neutral endopeptidase, NEP, enkephalinase, CD10, CALLA, EC 3.4.24.11), endothelin-converting enzyme I (ECE-1, EC 3.4.24.71), erythrocyte surface antigen KELL (ECE-3), phosphate-regulating gene on the X chromosome (PHEX), soluble secreted endopeptidase (SEP), and damage-induced neuronal endopeptidase (DINE)/X-converting enzyme (XCE). These proteins consist of a short N-terminal cytoplasmic domain, a single transmembrane helix, and a larger C-terminal extracellular domain containing the active site. Proteins in this family fulfill a broad range of physiological roles due to the greater variation in the S2' subsite allowing substrate specificity. NEP is expressed in a variety of tissues including kidney and brain, and is involved in many physiological and pathological processes, including blood pressure and inflammatory response. It degrades a wide array of substrates such as substance P, enkephalins, cholecystokinin, neurotensin and somatostatin. It is an important enzyme in the regulation of amyloid-beta (Abeta) protein that forms amyloid plaques that are associated with Alzeimers disease (AD). ECE-1 catalyzes the final rate-limiting step in the biosynthesis of endothelins via post-translational conversion of the biologically inactive big endothelins. Like NEP, it also hydrolyses bradykinin, substance P, neurotensin and Abeta. Endothelin-1 overproduction has been implicated in various diseases, including stroke, asthma, hypertension, and cardiac and renal failure. Kell is a homolog of NEP and constitutes a major antigen on human erythrocytes; it preferentially cleaves big endothelin-3 to produce bioactive endothelin-3, but is also known to cleave substance P and neurokinin A. PHEX forms a complex interaction with fibroblast growth factor 23 (FGF23) and matrix extracellular phosphoglycoprotein, causing bone mineralization. A loss-of-function mutation in PHEX disrupts this interaction leading to hypophosphatemic rickets; X-linked hypophosphatemic (XLH) rickets is the most common form of metabolic rickets. ECEL1 is a brain metalloprotease involved in the critical role in the nervous regulation of the respiratory system, while DINE (damage induced neuronal endopeptidase) is abundantly expressed in the hypothalamus and its expression responds to nerve injury as well. Thus, majority of these M13 proteases are prime therapeutic targets for selective inhibition.


:

Pssm-ID: 189000 [Multi-domain]  Cd Length: 611  Bit Score: 727.18  E-value: 0e+00
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592  74 VDPCDNFFRFACDGWISNNPIPEDMPSYGVYPWLRHNVDLKLKELLEKSISRRR-DTEAIQKAKILYSSCMNEKAIEKAD 152
Cdd:cd08662   1 VDPCDDFYQYACGNWLKNHPIPADKSSYGSFSELREKVEERLKEILEEAAAEKAsDSSAEQKIKDFYRSCMDTEAIEALG 80
                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592 153 AKPLLHILrhspfrwpvlesnigpegvwserkfsllqtlatfrgqysnsvfIRLYVSPDDKASNEHILKLDQATLSLAVR 232
Cdd:cd08662  81 LKPLLPLL-------------------------------------------FGLGVSPDLKNSSRNILYLDQPGLGLPDR 117
                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592 233 EDYLDNstEAKSYRDALYKFMVDTAVLLGANSSRAEHDMKSVLRLEIKIAEIMIP-HENRTSEAMYNKMNISELSAMIPQ 311
Cdd:cd08662 118 DYYLDE--KSKKIRAAYKAYLAKLLVLAGEDEEDAEALAEEVLAFETELAKISWSeEERRDPEKTYNPMTLAELQKLAPG 195
                       250       260       270       280       290       300       310       320
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592 312 FDWLGYIKKVIDTrlyphlkdiSPSENVVVRVPQYFKDLFRILGSERKKTIANYLVWRMVYSRIPNLSRRFQYRWLEFSR 391
Cdd:cd08662 196 IDWKAYLEALGLP---------SEDEKVIVTQPDYLKKLNKLLASTPLRTLKNYLIWRLLDSLAPYLSEEFRDANFFYGK 266
                       330       340       350       360       370       380       390       400
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592 392 VIQGTTTLLPQWDKCVNFIESALPYVVGKMFVDVYFQEDKKEMMEELVEGVRWAFIDMLEkENEWMDAGTKRKAKEKARA 471
Cdd:cd08662 267 TLSGTKEQRPRWKRCVSLVNGLLGEALGRLYVRKYFPPEAKARVEELVENLKKAFRERLE-NLDWMDEETKKKALEKLDA 345
                       410       420       430       440       450       460       470       480
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592 472 VLAKVGYPEFIMNDTHVNEDLKaikfSEADYFGNVLQTRKYLAQSDFFWLRKAVPKTEWFTNPTTVNAFYSASTNQIRFP 551
Cdd:cd08662 346 MTVKIGYPDKWRDYSKLDIDYD----DLDSYFGNVLRLRRFELERNLAKLGKPVDRTEWGMTPQTVNAYYNPTQNEIVFP 421
                       490       500       510       520       530       540       550       560
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592 552 AGELQKPFFwGTEYPRSLSYGAIGVIVGHEFTHGFDNNGRKYDKNGNLDPWWSTESEEKFKEKTKCMINQYSNYYWKKaG 631
Cdd:cd08662 422 AGILQPPFF-DPDAPDAVNYGGIGAVIGHEITHGFDDQGRQFDEDGNLRNWWTPEDRKAFEERTQCLVDQYSNYEVPP-G 499
                       570       580       590       600       610       620       630       640
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592 632 LNVKGKRTLGENIADNGGLREAFRAYRKWINDRrqglEEPLLPGITFTNNQLFFLSYAHVRCNSYRPEAAREQVQIGAHS 711
Cdd:cd08662 500 LHVNGKLTLGENIADLGGLRLAYDAYKKWLKGK----GAELPPGDGFTPDQLFFLSFAQVWCSKYRPEALRQLLLTDPHS 575
                       650       660       670
                ....*....|....*....|....*....|....*.
gi 90403592 712 PPQFRVNGAISNFEEFQKAFNCPPNSTMNRGMDSCR 747
Cdd:cd08662 576 PGKFRVNGVLSNSPEFAEAFNCPPGDPYMNPEKRCR 611
PepO COG3590
Predicted metalloendopeptidase [Posttranslational modification, protein turnover, chaperones]; ...
67-741 4.76e-128

Predicted metalloendopeptidase [Posttranslational modification, protein turnover, chaperones];


:

Pssm-ID: 226118 [Multi-domain]  Cd Length: 654  Bit Score: 398.33  E-value: 4.76e-128
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592  67 LSKVNLSVDPCDNFFRFACDGWISNNPIPEDMPSYGVYPWLRHNVDLKLKELLEKSISRRRDTEAIQKAKI--LYSSCMN 144
Cdd:COG3590  11 LSHMDAMTRPQDDLYGYVNGEWLKTAEIPADRSRDGAFDKLDDRAEALVRDIIEAAAANEQAPEDAILQRIgkLYRSFMD 90
                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592 145 EKAIEKADAKPLLHILRhspfRWPVLESnigpegvwserkFSLLQTLATFRGQYSNSVFIRLYVSPDDKASNEHILKLDQ 224
Cdd:COG3590  91 EAKREKAGVDPLKPELA----EIDSLAS------------FSDFAAALGQLERAGQGNPFGFSVSPDFKDSTRYVLYFSQ 154
                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592 225 ATLSLAVREDYLDNSTEAKsyRDALYKFMVDTAVLLGANSSRAEHDMKS--VLRLEIKIAEImipHEN----RTSEAMYN 298
Cdd:COG3590 155 SGLGLPDTTYYRDEQHAEL--LAAYKEHVARMLGLFGFSEEEEDAAKHAlrVVALETKLANA---SWEvvkyRDLYHTYN 229
                       250       260       270       280       290       300       310       320
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592 299 KMNISELSAMIPQFDWlGYIKKVIDTRlyphlkdisPSENVVVRVPQYFKDLFRILGSERKKTIANYLVWRMVYSRIPNL 378
Cdd:COG3590 230 PATFAELQPELPGDDW-SLLFSALGQL---------PDKVIVVENPFYLKEFASLLAEENWADWKAWLRWKLIRAAAPYL 299
                       330       340       350       360       370       380       390       400
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592 379 SRRFQYRWLEF-SRVIQGTTTLLPQWDKCVNFIESALPYVVGKMFVDVYFQEDKKEMMEELVEGVRWAFIDMLEKeNEWM 457
Cdd:COG3590 300 TEDLVDEHFDFyGRTLSGQPEARDRWKRAVNLAERLFGEAIGLLYVKRYFPPEAKADMEELVANLIKAYKARISK-LDWM 378
                       410       420       430       440       450       460       470       480
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592 458 DAGTKRKAKEKARAVLAKVGYPEfimndthVNEDLKAIKFSEADYFGNVLQTRKYLAQSDFFWLRKAVPKTEWFTNPTTV 537
Cdd:COG3590 379 TPETREKALEKLNKFTAKIGYPD-------PWRYYSKLEIKRDSLYGNVLRASAFNHAHELSKIGKPVDRDEWEMPPQTV 451
                       490       500       510       520       530       540       550       560
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592 538 NAFYSASTNQIRFPAGELQKPFFwGTEYPRSLSYGAIGVIVGHEFTHGFDNNGRKYDKNGNLDPWWSTESEEKFKEKTKC 617
Cdd:COG3590 452 NAYYNPQKNEIVFPAAILQAPFF-DPEADSAANYGGIGAVIGHEIGHGFDDQGAKFDGDGNLNDWWTDEDAAAFKERTKK 530
                       570       580       590       600       610       620       630       640
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592 618 MINQYsNYYWKKAGLNVKGKRTLGENIADNGGLREAFRAYRKWINdrrqglEEPLLPGitFTNNQLFFLSYAHVRCNSYR 697
Cdd:COG3590 531 LVAQF-DGYEPEGGKDNGNALTVGENIADLGGLAIALDAYKLSLD------PAPVIDG--FTGLQRFFLNWAQIWRMKAR 601
                       650       660       670       680
                ....*....|....*....|....*....|....*....|....
gi 90403592 698 PEAAREQVQIGAHSPPQFRVNGAISNFEEFQKAFNCPPNSTMNR 741
Cdd:COG3590 602 PEEQQMRLSVDPHSPAEFRVNGPVRNMDEFYEAFDVKEGDAMYR 645
 
Name Accession Description Interval E-value
M13 cd08662
Peptidase family M13 includes neprilysin, endothelin-converting enzyme I; M13 family of ...
74-747 0e+00

Peptidase family M13 includes neprilysin, endothelin-converting enzyme I; M13 family of metallopeptidases includes neprilysin (neutral endopeptidase, NEP, enkephalinase, CD10, CALLA, EC 3.4.24.11), endothelin-converting enzyme I (ECE-1, EC 3.4.24.71), erythrocyte surface antigen KELL (ECE-3), phosphate-regulating gene on the X chromosome (PHEX), soluble secreted endopeptidase (SEP), and damage-induced neuronal endopeptidase (DINE)/X-converting enzyme (XCE). These proteins consist of a short N-terminal cytoplasmic domain, a single transmembrane helix, and a larger C-terminal extracellular domain containing the active site. Proteins in this family fulfill a broad range of physiological roles due to the greater variation in the S2' subsite allowing substrate specificity. NEP is expressed in a variety of tissues including kidney and brain, and is involved in many physiological and pathological processes, including blood pressure and inflammatory response. It degrades a wide array of substrates such as substance P, enkephalins, cholecystokinin, neurotensin and somatostatin. It is an important enzyme in the regulation of amyloid-beta (Abeta) protein that forms amyloid plaques that are associated with Alzeimers disease (AD). ECE-1 catalyzes the final rate-limiting step in the biosynthesis of endothelins via post-translational conversion of the biologically inactive big endothelins. Like NEP, it also hydrolyses bradykinin, substance P, neurotensin and Abeta. Endothelin-1 overproduction has been implicated in various diseases, including stroke, asthma, hypertension, and cardiac and renal failure. Kell is a homolog of NEP and constitutes a major antigen on human erythrocytes; it preferentially cleaves big endothelin-3 to produce bioactive endothelin-3, but is also known to cleave substance P and neurokinin A. PHEX forms a complex interaction with fibroblast growth factor 23 (FGF23) and matrix extracellular phosphoglycoprotein, causing bone mineralization. A loss-of-function mutation in PHEX disrupts this interaction leading to hypophosphatemic rickets; X-linked hypophosphatemic (XLH) rickets is the most common form of metabolic rickets. ECEL1 is a brain metalloprotease involved in the critical role in the nervous regulation of the respiratory system, while DINE (damage induced neuronal endopeptidase) is abundantly expressed in the hypothalamus and its expression responds to nerve injury as well. Thus, majority of these M13 proteases are prime therapeutic targets for selective inhibition.


Pssm-ID: 189000 [Multi-domain]  Cd Length: 611  Bit Score: 727.18  E-value: 0e+00
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592  74 VDPCDNFFRFACDGWISNNPIPEDMPSYGVYPWLRHNVDLKLKELLEKSISRRR-DTEAIQKAKILYSSCMNEKAIEKAD 152
Cdd:cd08662   1 VDPCDDFYQYACGNWLKNHPIPADKSSYGSFSELREKVEERLKEILEEAAAEKAsDSSAEQKIKDFYRSCMDTEAIEALG 80
                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592 153 AKPLLHILrhspfrwpvlesnigpegvwserkfsllqtlatfrgqysnsvfIRLYVSPDDKASNEHILKLDQATLSLAVR 232
Cdd:cd08662  81 LKPLLPLL-------------------------------------------FGLGVSPDLKNSSRNILYLDQPGLGLPDR 117
                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592 233 EDYLDNstEAKSYRDALYKFMVDTAVLLGANSSRAEHDMKSVLRLEIKIAEIMIP-HENRTSEAMYNKMNISELSAMIPQ 311
Cdd:cd08662 118 DYYLDE--KSKKIRAAYKAYLAKLLVLAGEDEEDAEALAEEVLAFETELAKISWSeEERRDPEKTYNPMTLAELQKLAPG 195
                       250       260       270       280       290       300       310       320
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592 312 FDWLGYIKKVIDTrlyphlkdiSPSENVVVRVPQYFKDLFRILGSERKKTIANYLVWRMVYSRIPNLSRRFQYRWLEFSR 391
Cdd:cd08662 196 IDWKAYLEALGLP---------SEDEKVIVTQPDYLKKLNKLLASTPLRTLKNYLIWRLLDSLAPYLSEEFRDANFFYGK 266
                       330       340       350       360       370       380       390       400
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592 392 VIQGTTTLLPQWDKCVNFIESALPYVVGKMFVDVYFQEDKKEMMEELVEGVRWAFIDMLEkENEWMDAGTKRKAKEKARA 471
Cdd:cd08662 267 TLSGTKEQRPRWKRCVSLVNGLLGEALGRLYVRKYFPPEAKARVEELVENLKKAFRERLE-NLDWMDEETKKKALEKLDA 345
                       410       420       430       440       450       460       470       480
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592 472 VLAKVGYPEFIMNDTHVNEDLKaikfSEADYFGNVLQTRKYLAQSDFFWLRKAVPKTEWFTNPTTVNAFYSASTNQIRFP 551
Cdd:cd08662 346 MTVKIGYPDKWRDYSKLDIDYD----DLDSYFGNVLRLRRFELERNLAKLGKPVDRTEWGMTPQTVNAYYNPTQNEIVFP 421
                       490       500       510       520       530       540       550       560
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592 552 AGELQKPFFwGTEYPRSLSYGAIGVIVGHEFTHGFDNNGRKYDKNGNLDPWWSTESEEKFKEKTKCMINQYSNYYWKKaG 631
Cdd:cd08662 422 AGILQPPFF-DPDAPDAVNYGGIGAVIGHEITHGFDDQGRQFDEDGNLRNWWTPEDRKAFEERTQCLVDQYSNYEVPP-G 499
                       570       580       590       600       610       620       630       640
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592 632 LNVKGKRTLGENIADNGGLREAFRAYRKWINDRrqglEEPLLPGITFTNNQLFFLSYAHVRCNSYRPEAAREQVQIGAHS 711
Cdd:cd08662 500 LHVNGKLTLGENIADLGGLRLAYDAYKKWLKGK----GAELPPGDGFTPDQLFFLSFAQVWCSKYRPEALRQLLLTDPHS 575
                       650       660       670
                ....*....|....*....|....*....|....*.
gi 90403592 712 PPQFRVNGAISNFEEFQKAFNCPPNSTMNRGMDSCR 747
Cdd:cd08662 576 PGKFRVNGVLSNSPEFAEAFNCPPGDPYMNPEKRCR 611
Peptidase_M13 pfam01431
Peptidase family M13; Mammalian enzymes are typically type-II membrane anchored enzymes which ...
538-748 3.38e-77

Peptidase family M13; Mammalian enzymes are typically type-II membrane anchored enzymes which are known, or believed to activate or inactivate oligopeptide (pro)-hormones such as opioid peptides. The family also contains a bacterial member believed to be involved with milk protein cleavage.


Pssm-ID: 279739  Cd Length: 205  Bit Score: 249.25  E-value: 3.38e-77
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592   538 NAFYSASTNQIRFPAGELQKPFFwGTEYPRSLSYGAIGVIVGHEFTHGFDNNGRKYDKNGNLDPWWSTESEEKFKEKTKC 617
Cdd:pfam01431   1 NAYYQPNRNEIVFPAAILQPPFF-DPNYPRAVNYGGIGNVIAHEITHGFDDQGAQFDKDGNLRSWWTDEDAEEFKDRAQC 79
                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592   618 MINQYSNYYWKKAGLNVKGKRTLGENIADNGGLREAFRAYRKwindrRQGLEEPLLPGI-TFTNNQLFFLSYAHVRCNSY 696
Cdd:pfam01431  80 LIEQYSEYTPPDGTKCANGTLTLGENIADLGGLTIALRAYKK-----LLSANETVLPGFeNLTPDQLFFRGAAQIWCMKQ 154
                         170       180       190       200       210
                  ....*....|....*....|....*....|....*....|....*....|..
gi 90403592   697 RPEAAREQVQIGAHSPPQFRVNGAISNFEEFQKAFNCPPNSTMNRGmDSCRL 748
Cdd:pfam01431 155 SPAEVLRQLLVDPHSPPEFRVNGVMSNMPAFYEAFNCPEGDKMNPE-PRCRL 205
PepO COG3590
Predicted metalloendopeptidase [Posttranslational modification, protein turnover, chaperones]; ...
67-741 4.76e-128

Predicted metalloendopeptidase [Posttranslational modification, protein turnover, chaperones];


Pssm-ID: 226118 [Multi-domain]  Cd Length: 654  Bit Score: 398.33  E-value: 4.76e-128
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592  67 LSKVNLSVDPCDNFFRFACDGWISNNPIPEDMPSYGVYPWLRHNVDLKLKELLEKSISRRRDTEAIQKAKI--LYSSCMN 144
Cdd:COG3590  11 LSHMDAMTRPQDDLYGYVNGEWLKTAEIPADRSRDGAFDKLDDRAEALVRDIIEAAAANEQAPEDAILQRIgkLYRSFMD 90
                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592 145 EKAIEKADAKPLLHILRhspfRWPVLESnigpegvwserkFSLLQTLATFRGQYSNSVFIRLYVSPDDKASNEHILKLDQ 224
Cdd:COG3590  91 EAKREKAGVDPLKPELA----EIDSLAS------------FSDFAAALGQLERAGQGNPFGFSVSPDFKDSTRYVLYFSQ 154
                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592 225 ATLSLAVREDYLDNSTEAKsyRDALYKFMVDTAVLLGANSSRAEHDMKS--VLRLEIKIAEImipHEN----RTSEAMYN 298
Cdd:COG3590 155 SGLGLPDTTYYRDEQHAEL--LAAYKEHVARMLGLFGFSEEEEDAAKHAlrVVALETKLANA---SWEvvkyRDLYHTYN 229
                       250       260       270       280       290       300       310       320
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592 299 KMNISELSAMIPQFDWlGYIKKVIDTRlyphlkdisPSENVVVRVPQYFKDLFRILGSERKKTIANYLVWRMVYSRIPNL 378
Cdd:COG3590 230 PATFAELQPELPGDDW-SLLFSALGQL---------PDKVIVVENPFYLKEFASLLAEENWADWKAWLRWKLIRAAAPYL 299
                       330       340       350       360       370       380       390       400
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592 379 SRRFQYRWLEF-SRVIQGTTTLLPQWDKCVNFIESALPYVVGKMFVDVYFQEDKKEMMEELVEGVRWAFIDMLEKeNEWM 457
Cdd:COG3590 300 TEDLVDEHFDFyGRTLSGQPEARDRWKRAVNLAERLFGEAIGLLYVKRYFPPEAKADMEELVANLIKAYKARISK-LDWM 378
                       410       420       430       440       450       460       470       480
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592 458 DAGTKRKAKEKARAVLAKVGYPEfimndthVNEDLKAIKFSEADYFGNVLQTRKYLAQSDFFWLRKAVPKTEWFTNPTTV 537
Cdd:COG3590 379 TPETREKALEKLNKFTAKIGYPD-------PWRYYSKLEIKRDSLYGNVLRASAFNHAHELSKIGKPVDRDEWEMPPQTV 451
                       490       500       510       520       530       540       550       560
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592 538 NAFYSASTNQIRFPAGELQKPFFwGTEYPRSLSYGAIGVIVGHEFTHGFDNNGRKYDKNGNLDPWWSTESEEKFKEKTKC 617
Cdd:COG3590 452 NAYYNPQKNEIVFPAAILQAPFF-DPEADSAANYGGIGAVIGHEIGHGFDDQGAKFDGDGNLNDWWTDEDAAAFKERTKK 530
                       570       580       590       600       610       620       630       640
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592 618 MINQYsNYYWKKAGLNVKGKRTLGENIADNGGLREAFRAYRKWINdrrqglEEPLLPGitFTNNQLFFLSYAHVRCNSYR 697
Cdd:COG3590 531 LVAQF-DGYEPEGGKDNGNALTVGENIADLGGLAIALDAYKLSLD------PAPVIDG--FTGLQRFFLNWAQIWRMKAR 601
                       650       660       670       680
                ....*....|....*....|....*....|....*....|....
gi 90403592 698 PEAAREQVQIGAHSPPQFRVNGAISNFEEFQKAFNCPPNSTMNR 741
Cdd:COG3590 602 PEEQQMRLSVDPHSPAEFRVNGPVRNMDEFYEAFDVKEGDAMYR 645
 
Name Accession Description Interval E-value
M13 cd08662
Peptidase family M13 includes neprilysin, endothelin-converting enzyme I; M13 family of ...
74-747 0e+00

Peptidase family M13 includes neprilysin, endothelin-converting enzyme I; M13 family of metallopeptidases includes neprilysin (neutral endopeptidase, NEP, enkephalinase, CD10, CALLA, EC 3.4.24.11), endothelin-converting enzyme I (ECE-1, EC 3.4.24.71), erythrocyte surface antigen KELL (ECE-3), phosphate-regulating gene on the X chromosome (PHEX), soluble secreted endopeptidase (SEP), and damage-induced neuronal endopeptidase (DINE)/X-converting enzyme (XCE). These proteins consist of a short N-terminal cytoplasmic domain, a single transmembrane helix, and a larger C-terminal extracellular domain containing the active site. Proteins in this family fulfill a broad range of physiological roles due to the greater variation in the S2' subsite allowing substrate specificity. NEP is expressed in a variety of tissues including kidney and brain, and is involved in many physiological and pathological processes, including blood pressure and inflammatory response. It degrades a wide array of substrates such as substance P, enkephalins, cholecystokinin, neurotensin and somatostatin. It is an important enzyme in the regulation of amyloid-beta (Abeta) protein that forms amyloid plaques that are associated with Alzeimers disease (AD). ECE-1 catalyzes the final rate-limiting step in the biosynthesis of endothelins via post-translational conversion of the biologically inactive big endothelins. Like NEP, it also hydrolyses bradykinin, substance P, neurotensin and Abeta. Endothelin-1 overproduction has been implicated in various diseases, including stroke, asthma, hypertension, and cardiac and renal failure. Kell is a homolog of NEP and constitutes a major antigen on human erythrocytes; it preferentially cleaves big endothelin-3 to produce bioactive endothelin-3, but is also known to cleave substance P and neurokinin A. PHEX forms a complex interaction with fibroblast growth factor 23 (FGF23) and matrix extracellular phosphoglycoprotein, causing bone mineralization. A loss-of-function mutation in PHEX disrupts this interaction leading to hypophosphatemic rickets; X-linked hypophosphatemic (XLH) rickets is the most common form of metabolic rickets. ECEL1 is a brain metalloprotease involved in the critical role in the nervous regulation of the respiratory system, while DINE (damage induced neuronal endopeptidase) is abundantly expressed in the hypothalamus and its expression responds to nerve injury as well. Thus, majority of these M13 proteases are prime therapeutic targets for selective inhibition.


Pssm-ID: 189000 [Multi-domain]  Cd Length: 611  Bit Score: 727.18  E-value: 0e+00
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592  74 VDPCDNFFRFACDGWISNNPIPEDMPSYGVYPWLRHNVDLKLKELLEKSISRRR-DTEAIQKAKILYSSCMNEKAIEKAD 152
Cdd:cd08662   1 VDPCDDFYQYACGNWLKNHPIPADKSSYGSFSELREKVEERLKEILEEAAAEKAsDSSAEQKIKDFYRSCMDTEAIEALG 80
                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592 153 AKPLLHILrhspfrwpvlesnigpegvwserkfsllqtlatfrgqysnsvfIRLYVSPDDKASNEHILKLDQATLSLAVR 232
Cdd:cd08662  81 LKPLLPLL-------------------------------------------FGLGVSPDLKNSSRNILYLDQPGLGLPDR 117
                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592 233 EDYLDNstEAKSYRDALYKFMVDTAVLLGANSSRAEHDMKSVLRLEIKIAEIMIP-HENRTSEAMYNKMNISELSAMIPQ 311
Cdd:cd08662 118 DYYLDE--KSKKIRAAYKAYLAKLLVLAGEDEEDAEALAEEVLAFETELAKISWSeEERRDPEKTYNPMTLAELQKLAPG 195
                       250       260       270       280       290       300       310       320
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592 312 FDWLGYIKKVIDTrlyphlkdiSPSENVVVRVPQYFKDLFRILGSERKKTIANYLVWRMVYSRIPNLSRRFQYRWLEFSR 391
Cdd:cd08662 196 IDWKAYLEALGLP---------SEDEKVIVTQPDYLKKLNKLLASTPLRTLKNYLIWRLLDSLAPYLSEEFRDANFFYGK 266
                       330       340       350       360       370       380       390       400
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592 392 VIQGTTTLLPQWDKCVNFIESALPYVVGKMFVDVYFQEDKKEMMEELVEGVRWAFIDMLEkENEWMDAGTKRKAKEKARA 471
Cdd:cd08662 267 TLSGTKEQRPRWKRCVSLVNGLLGEALGRLYVRKYFPPEAKARVEELVENLKKAFRERLE-NLDWMDEETKKKALEKLDA 345
                       410       420       430       440       450       460       470       480
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592 472 VLAKVGYPEFIMNDTHVNEDLKaikfSEADYFGNVLQTRKYLAQSDFFWLRKAVPKTEWFTNPTTVNAFYSASTNQIRFP 551
Cdd:cd08662 346 MTVKIGYPDKWRDYSKLDIDYD----DLDSYFGNVLRLRRFELERNLAKLGKPVDRTEWGMTPQTVNAYYNPTQNEIVFP 421
                       490       500       510       520       530       540       550       560
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592 552 AGELQKPFFwGTEYPRSLSYGAIGVIVGHEFTHGFDNNGRKYDKNGNLDPWWSTESEEKFKEKTKCMINQYSNYYWKKaG 631
Cdd:cd08662 422 AGILQPPFF-DPDAPDAVNYGGIGAVIGHEITHGFDDQGRQFDEDGNLRNWWTPEDRKAFEERTQCLVDQYSNYEVPP-G 499
                       570       580       590       600       610       620       630       640
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592 632 LNVKGKRTLGENIADNGGLREAFRAYRKWINDRrqglEEPLLPGITFTNNQLFFLSYAHVRCNSYRPEAAREQVQIGAHS 711
Cdd:cd08662 500 LHVNGKLTLGENIADLGGLRLAYDAYKKWLKGK----GAELPPGDGFTPDQLFFLSFAQVWCSKYRPEALRQLLLTDPHS 575
                       650       660       670
                ....*....|....*....|....*....|....*.
gi 90403592 712 PPQFRVNGAISNFEEFQKAFNCPPNSTMNRGMDSCR 747
Cdd:cd08662 576 PGKFRVNGVLSNSPEFAEAFNCPPGDPYMNPEKRCR 611
Peptidase_M13 pfam01431
Peptidase family M13; Mammalian enzymes are typically type-II membrane anchored enzymes which ...
538-748 3.38e-77

Peptidase family M13; Mammalian enzymes are typically type-II membrane anchored enzymes which are known, or believed to activate or inactivate oligopeptide (pro)-hormones such as opioid peptides. The family also contains a bacterial member believed to be involved with milk protein cleavage.


Pssm-ID: 279739  Cd Length: 205  Bit Score: 249.25  E-value: 3.38e-77
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592   538 NAFYSASTNQIRFPAGELQKPFFwGTEYPRSLSYGAIGVIVGHEFTHGFDNNGRKYDKNGNLDPWWSTESEEKFKEKTKC 617
Cdd:pfam01431   1 NAYYQPNRNEIVFPAAILQPPFF-DPNYPRAVNYGGIGNVIAHEITHGFDDQGAQFDKDGNLRSWWTDEDAEEFKDRAQC 79
                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592   618 MINQYSNYYWKKAGLNVKGKRTLGENIADNGGLREAFRAYRKwindrRQGLEEPLLPGI-TFTNNQLFFLSYAHVRCNSY 696
Cdd:pfam01431  80 LIEQYSEYTPPDGTKCANGTLTLGENIADLGGLTIALRAYKK-----LLSANETVLPGFeNLTPDQLFFRGAAQIWCMKQ 154
                         170       180       190       200       210
                  ....*....|....*....|....*....|....*....|....*....|..
gi 90403592   697 RPEAAREQVQIGAHSPPQFRVNGAISNFEEFQKAFNCPPNSTMNRGmDSCRL 748
Cdd:pfam01431 155 SPAEVLRQLLVDPHSPPEFRVNGVMSNMPAFYEAFNCPEGDKMNPE-PRCRL 205
Peptidase_M13_N pfam05649
Peptidase family M13; M13 peptidases are well-studied proteases found in a wide range of ...
77-479 8.91e-72

Peptidase family M13; M13 peptidases are well-studied proteases found in a wide range of organizms including mammals and bacteria. In mammals they participate in processes such as cardiovascular development, blood-pressure regulation, nervous control of respiration, and regulation of the function of neuropeptides in the central nervous system. In bacteria they may be used for digestion of milk.


Pssm-ID: 283336  Cd Length: 269  Bit Score: 236.85  E-value: 8.91e-72
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592    77 CDNFFRFACDGWISNNPIPEDMPSYGVYPWLRHNVDLKLKELLEKSISRRRDTEAiQKAKILYSSCMNEKAIEKADAKPL 156
Cdd:pfam05649   1 CDDFYEYACGGWLKNNPIPADKSSWGSFSELRERNEKILRELLEAPAPADSDSEA-QKAKDFYRSCMDTDAIEALGLKPL 79
                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592   157 LHILRHspfrwpvlesnIGPegvwSERKFSLLQTLATFRgqysnSVFIRLYVSPDdkasnehILKLdqatlslavredYL 236
Cdd:pfam05649  80 KPLLDE-----------IGA----LKSKFDLTETLARLG-----RTLFGFGVDPD-------LAKL------------YL 120
                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592   237 DNSTEaksyrdalykfmvdtavllganssraehdmksvlrleikiaeimiphenrtseamynkmniselsamipqfdwlg 316
Cdd:pfam05649 121 KALGL--------------------------------------------------------------------------- 125
                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592   317 yikkvidtrlyphlkdisPSENVVVRVPQYFKDLFRILGSERKKTIANYLVWRMVYSRIPNLSRRFQYRWLEFSRVIQGT 396
Cdd:pfam05649 126 ------------------PPEEVIVTDPDYLKNLSKLLSTTPLRTLKNYLIWRLVRSLAPYLSDEFRDANFEFGKALSGT 187
                         330       340       350       360       370       380       390       400
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592   397 TTLLPQWDKCVNFIESALPYVVGKMFVDVYFQEDKKEMMEELVEGVRWAFIDMLEkENEWMDAGTKRKAKEKARAVLAKV 476
Cdd:pfam05649 188 KEQRPRWKRCVSLVNGALGEALGRLYVRKYFPEEAKADAEELVSNIKEAFKERLE-ELDWMDDETKKKALEKLDAMTVKI 266

                  ...
gi 90403592   477 GYP 479
Cdd:pfam05649 267 GYP 269
GluZincin cd09594
Peptidase Gluzincin family (thermolysin-like proteinases, TLPs) includes peptidases M1, M2, M3, ...
507-597 2.70e-04

Peptidase Gluzincin family (thermolysin-like proteinases, TLPs) includes peptidases M1, M2, M3, M4, M13, M32 and M36 (fungalysins); Gluzincin family (thermolysin-like peptidases or TLPs) includes several zinc-dependent metallopeptidases such as the M1, M2, M3, M4, M13, M32, M36 peptidases (MEROPS classification), and contain HEXXH and EXXXD motifs as part of their active site. All peptidases in this family bind a single catalytic zinc ion which is tetrahedrally co-ordinated by three amino acid ligands and a water molecule that forms the nucleophile on activation during catalysis. M1 family includes aminopeptidase N (APN) and leukotriene A4 hydrolase (LTA4H). APN preferentially cleaves neutral amino acids from the N-terminus of oligopeptides and is present in a variety of human tissues and cell types. LTA4H is a bifunctional enzyme, possessing an aminopeptidase as well as an epoxide hydrolase activity such that the two activities occupy different, but overlapping sites. The peptidase M3 or neurolysin-like family, includes M3, M2 and M32 metallopeptidases. The M3 peptidases have two subfamilies: M3A, includes thimet oligopeptidase (TOP; endopeptidase 3.4.24.15), neurolysin (3.4.24.16), and the mitochondrial intermediate peptidase; M3B contains oligopeptidase F. M2 peptidase angiotensin converting enzyme (ACE, EC 3.4.15.1) catalyzes the conversion of decapeptide angiotensin I to the potent vasopressor octapeptide angiotensin II. ACE is a key part of the renin-angiotensin system that regulates blood pressure, thus ACE inhibitors are important for the treatment of hypertension. M32 family includes two eukaryotic enzymes from protozoa Trypanosoma cruzi, a causative agent of Chagas' disease, and Leishmania major, a parasite that causes leishmaniasis, making them attractive targets for drug development. The M4 family includes secreted protease thermolysin (EC 3.4.24.27), pseudolysin, aureolysin, neutral protease as well as fungalysin and bacillolysin (EC 3.4.24.28) that degrade extracellular proteins and peptides for bacterial nutrition, especially prior to sporulation. Thermolysin is widely used as a nonspecific protease to obtain fragments for peptide sequencing as well as in production of the artificial sweetener aspartame. M13 family includes neprilysin (EC 3.4.24.11) and endothelin-converting enzyme I (ECE-1, EC 3.4.24.71), which fulfill a broad range of physiological roles due to the greater variation in the S2' subsite allowing substrate specificity and are prime therapeutic targets for selective inhibition. Peptidase M36 (fungamysin) family includes endopeptidases from pathogenic fungi. Fungalysin hydrolyzes extracellular matrix proteins such as elastin and keratin. Aspergillus fumigatus causes the pulmonary disease aspergillosis by invading the lungs of immuno-compromised animals and secreting fungalysin that possibly breaks down proteinaceous structural barriers.


Pssm-ID: 189001  Cd Length: 125  Bit Score: 40.13  E-value: 2.70e-04
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592 507 LQTRKYLAQSDF--FWLRKAVPKTEWFTNPTT----VNAFYSASTNQIRFPAGELQKPffwgteyprsLSYGAIGVIVGH 580
Cdd:cd09594   6 KETLKIYESLGGrnKTDEVGGGYYSMVYPPSNqgkvNNAMCNGLDARIVMNDGILVAF----------LLDSDDFGVVGH 75
                        90
                ....*....|....*..
gi 90403592 581 EFTHGFDNNGRKYDKNG 597
Cdd:cd09594  76 ELTHGVTDQLVGNDPDL 92
PepO COG3590
Predicted metalloendopeptidase [Posttranslational modification, protein turnover, chaperones]; ...
67-741 4.76e-128

Predicted metalloendopeptidase [Posttranslational modification, protein turnover, chaperones];


Pssm-ID: 226118 [Multi-domain]  Cd Length: 654  Bit Score: 398.33  E-value: 4.76e-128
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592  67 LSKVNLSVDPCDNFFRFACDGWISNNPIPEDMPSYGVYPWLRHNVDLKLKELLEKSISRRRDTEAIQKAKI--LYSSCMN 144
Cdd:COG3590  11 LSHMDAMTRPQDDLYGYVNGEWLKTAEIPADRSRDGAFDKLDDRAEALVRDIIEAAAANEQAPEDAILQRIgkLYRSFMD 90
                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592 145 EKAIEKADAKPLLHILRhspfRWPVLESnigpegvwserkFSLLQTLATFRGQYSNSVFIRLYVSPDDKASNEHILKLDQ 224
Cdd:COG3590  91 EAKREKAGVDPLKPELA----EIDSLAS------------FSDFAAALGQLERAGQGNPFGFSVSPDFKDSTRYVLYFSQ 154
                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592 225 ATLSLAVREDYLDNSTEAKsyRDALYKFMVDTAVLLGANSSRAEHDMKS--VLRLEIKIAEImipHEN----RTSEAMYN 298
Cdd:COG3590 155 SGLGLPDTTYYRDEQHAEL--LAAYKEHVARMLGLFGFSEEEEDAAKHAlrVVALETKLANA---SWEvvkyRDLYHTYN 229
                       250       260       270       280       290       300       310       320
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592 299 KMNISELSAMIPQFDWlGYIKKVIDTRlyphlkdisPSENVVVRVPQYFKDLFRILGSERKKTIANYLVWRMVYSRIPNL 378
Cdd:COG3590 230 PATFAELQPELPGDDW-SLLFSALGQL---------PDKVIVVENPFYLKEFASLLAEENWADWKAWLRWKLIRAAAPYL 299
                       330       340       350       360       370       380       390       400
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592 379 SRRFQYRWLEF-SRVIQGTTTLLPQWDKCVNFIESALPYVVGKMFVDVYFQEDKKEMMEELVEGVRWAFIDMLEKeNEWM 457
Cdd:COG3590 300 TEDLVDEHFDFyGRTLSGQPEARDRWKRAVNLAERLFGEAIGLLYVKRYFPPEAKADMEELVANLIKAYKARISK-LDWM 378
                       410       420       430       440       450       460       470       480
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592 458 DAGTKRKAKEKARAVLAKVGYPEfimndthVNEDLKAIKFSEADYFGNVLQTRKYLAQSDFFWLRKAVPKTEWFTNPTTV 537
Cdd:COG3590 379 TPETREKALEKLNKFTAKIGYPD-------PWRYYSKLEIKRDSLYGNVLRASAFNHAHELSKIGKPVDRDEWEMPPQTV 451
                       490       500       510       520       530       540       550       560
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592 538 NAFYSASTNQIRFPAGELQKPFFwGTEYPRSLSYGAIGVIVGHEFTHGFDNNGRKYDKNGNLDPWWSTESEEKFKEKTKC 617
Cdd:COG3590 452 NAYYNPQKNEIVFPAAILQAPFF-DPEADSAANYGGIGAVIGHEIGHGFDDQGAKFDGDGNLNDWWTDEDAAAFKERTKK 530
                       570       580       590       600       610       620       630       640
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 90403592 618 MINQYsNYYWKKAGLNVKGKRTLGENIADNGGLREAFRAYRKWINdrrqglEEPLLPGitFTNNQLFFLSYAHVRCNSYR 697
Cdd:COG3590 531 LVAQF-DGYEPEGGKDNGNALTVGENIADLGGLAIALDAYKLSLD------PAPVIDG--FTGLQRFFLNWAQIWRMKAR 601
                       650       660       670       680
                ....*....|....*....|....*....|....*....|....
gi 90403592 698 PEAAREQVQIGAHSPPQFRVNGAISNFEEFQKAFNCPPNSTMNR 741
Cdd:COG3590 602 PEEQQMRLSVDPHSPAEFRVNGPVRNMDEFYEAFDVKEGDAMYR 645
 
Blast search parameters
Data Source: Precalculated data, version = cdd.v.3.15
Preset Options:Database: CDSEARCH/cdd   Low complexity filter: no  Composition Based Adjustment: yes   E-value threshold: 0.01

References:

  • Marchler-Bauer A et al. (2015), "CDD: NCBI's conserved domain database.", Nucleic Acids Res.43(D)222-6.
  • Marchler-Bauer A et al. (2011), "CDD: a Conserved Domain Database for the functional annotation of proteins.", Nucleic Acids Res.39(D)225-9.
  • Marchler-Bauer A et al. (2009), "CDD: specific functional annotation with the Conserved Domain Database.", Nucleic Acids Res.37(D)205-10.
  • Marchler-Bauer A, Bryant SH (2004), "CD-Search: protein domain annotations on the fly.", Nucleic Acids Res.32(W)327-331.
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