Conserved Protein Domain Family
M13

?
cd08662: M13 
Click on image for an interactive view with Cn3D
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.
Statistics
?
PSSM-Id: 189000
View PSSM: cd08662
Aligned: 300 rows
Threshold Bit Score: 256.846
Threshold Setting Gi: 241859544
Created: 19-Nov-2009
Updated: 17-Jan-2013
Structure
?
Program:
Drawing:
Aligned Rows:
 
active siteZn binding site
Conserved site includes 11 residues -Click on image for an interactive view with Cn3D
Feature 1:active site [active site]
Evidence:

Sequence Alignment
?
Format: Row Display: Color Bits: Type Selection:
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
Feature 1                                                                                         
3DWB_A         19 VDPCHDFFSYACGGWIKANpvpdg----hsrwGTFSNLWEHNQAIIKHllensta---svseaerKAQVYYRACMNetri 91
1R1H_A         23 TEPCTDFFKYACGGWLKRNvipet----ssryGNFDILRDELEVVLKDvlqepkt---edivavqKAKALYRSCINesai 95
gi 34577157   181 VDPCEDFYAFTCNKYIKEHdpqel---gvgkfSPSKELQDDINAEIAEalrtvevnsqqwskterITKALLHSCVYhrts 257
gi 34577159   150 VDPCEDFYAFTCNTYLKNHnatei---gvnriGTYKDAQDDVNAEIVDaleavnvpdakwseterLVKATLFTCVHhira 226
gi 74966315    83 VDPCQDFYAFTCNKFLQNTdlqkl---grsrlGTYDQAQVDVYSEIVAalskidvtstttskterITKAAFETCKNnlas 159
gi 74893537   103 VDPCEDFYGFTCNKFIERIdldel---grgrfTTFSQAQLEVNSDIVKalekvdvndekfsqterITKAAFQSCVEytlk 179
gi 198451121   66 VAPCDDFYEYACGNWQHVKqdrqss-hkrsnlLDIGYTLGDVVELLLTknslamdl--nytaellIAQRFYNACLGadly 142
gi 24650765    66 VDPCDDFYEFACGNWKNVKtprqsp-hrrsniLDISYTLMDVTEQLLTrtklaeal--nvsaellVAQRFYNSCLAaelf 142
gi 194746370  732 VAPCDDFYEYACGNWKNVRpdhfqsnhkrsnlLDIVYTLRDEVEELLTsmqlaqal--nvstellVAQQFYNACLSavvf 809
gi 195444158   60 ISPCDDFYEYACGNWKNVQpdrrgl-hirgsaSDIIYTLGDVTENLLTksslaidl--nyekemqIAQKFYNACLRaelq 136
                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
Feature 1                                                                                         
3DWB_A         92 e---elraKPLMELIerlggwnitgpwakdnf------qdtlqvvtahyrtspfFSVYVSADSKnsnsnVIQVDQSglgl 162
1R1H_A         96 d---srggEPLLKLLpdiygwpvatenweqkygaswtaekaiaqlnskygkkvlINLFVGTDDKnsvnhVIHIDQPrlgl 172
gi 34577157   258 rtpidnmiDFLQEIKrlfggipfighplkdgfd----lfsamgdleqnhamgtlMGGMVSVDYKkdsqhALYISQPslpm 333
gi 34577159   227 rnpidnsrDVLIEMRelfggipflnhtlkkdid----ffditgkfeqnhamgslLGAMVSVDFEdvkkhSLFISQPylpm 302
gi 74966315   160 p--adktaVVYAEITslfggvpffgeplktnvd----ywmvagqieqkhavgtlTYTIASSDYKdhtknALYTGPPglsl 233
gi 74893537   180 ddrkasvnELLQYISerfggipflgqrvkggce----lyremgrieqqralptfMYTWVNVDHKnvsrnSYYISQPtlpm 255
gi 198451121  143 p---lpaaDPAYLALirsiggfpavdgeawha------anfswfnmsaqltnfgINGLIHEKILpqypfVPYFKVPelgf 213
gi 24650765   143 p---rpaaDPAYLSVirslggfpavdrdawna------ssfswfnmsahlsnygVRSLIHEEILpqhpfNPYFKLPelgf 213
gi 194746370  810 p---lpaaDPAYLALirsvggfpavdgpawna------stfswfnmsahltnygVSGLINEDNLpqypfNPFFKLPelgf 880
gi 195444158  137 p---lpatDPAYLTLiksiggfpavdgpewqa------dkfnwfnmsahltnygAKGLINERLMtvapfAPIFLKPelgf 207
                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
Feature 1                                                                                         
3DWB_A        163 psrdyyl------nktenekvltgYLNYMVQLGkllgggde-----eairpqmQQILDFETALANItipqek-rrdeelI 230
1R1H_A        173 psrdyye------ctgiykeactaYVDFMISVArlirqeerlpidenqlalemNKVMELEKEIANAtakped-rndpmlL 245
gi 34577157   334 prefyvlpqftkklqerekllrdvLFKFADTILddpepya------keikkaaLDIVQLERRIAMAswpktq-lrnyaqQ 406
gi 34577159   303 ardfyvfgqhtkmvenrvnlinsvLKSFAEAVLddpspyl------dlilrsaKDVVKLEMQIATAswpese-lrnfaqQ 375
gi 74966315   234 ardfyvkpqy-iaevnqrvsdvndLLTAFANAAkknvgad-------allaaaQEVVNFEVQIAMAswpddl-lrnyqqQ 304
gi 74893537   256 prefyvlpqfapeldartkaienvMKAFASDILkdpskyd------kmiktaaREVTQIEQKIAMAswpdde-lrnheqQ 328
gi 198451121  214 dyivhs--------dniasndtrgYKLNEKRMRgy-----------------lEAYGLSEEKVSQViaevfafwhdalvV 268
gi 24650765   214 dhvvht--------ahvantssraYQLNEHRMRgy-----------------lKEYNLTKDEISAViegvfafwsealsI 268
gi 194746370  881 dhivqt--------dnianntsraYKLNEKRMQty-----------------lQAYNLTEDKISEVisgvfafwrdalaV 935
gi 195444158  208 eykvys--------dnlvtneteaYKVNEQRMRvy-----------------lQSFGLAEEKISEViagvfafwhdvlnL 262
                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
Feature 1                                                                                         
3DWB_A        231 YHKVtaaelq--------tlapaINWLPFLNtifypve------inesepIVVYdKEYLEqist----lintTDRCLLNN 292
1R1H_A        246 YNKMtlaqiqnnf--sleingkpFSWLNFTNeimstvni----sitneedVVVYaPEYLTklkp----iltkYSARDLQN 315
gi 34577157   407 YNAYklrdlk--------ktypkINWDSYLNalmstagk---pdfsgsarLVIAqPSYFGwlnal--vsgntVDDKMLVN 473
gi 34577159   376 HNPRtldqlk--------kaypaIKWDSYFKallssvpn----vdisrqnIIVTqPSYFGwlnal---fsggADENTIAN 440
gi 74966315   305 YNPYniasat--------tayraINWKSYLGqlfhgvas---dadqanynIVVTePSYFAwlnsv--fdgktSNSTVVAN 371
gi 74893537   329 YNPYelfapsegk-ialqdafpnIRFGKYIAglmetatggvpvspvfigdVIVTnPAYMGflntlfrqtniqMNQYPFVN 407
gi 198451121  269 IDRFgddlkecedhaelndipsfSEWSSYYAiawnst--------nfpkeNIETfCDFYYveld----kvcaKHKPAVAN 336
gi 24650765   269 EDKFesdrdkcdllseieevprfGQWRSYYEiawngi-------dfyngsSGGEfCDFYYveld----kvcaKHTEAVAN 337
gi 194746370  936 ADKFdgkeekcfevsetenvskyHQWDSYYEiawngq-------nfssvgGMDGyCDYYYkqld----nvcsRHPEAVAN 1004
gi 195444158  263 NDRFpedltectqksylrkytqfKHWSNYFEiawng---------enftlDKPFaCDPYYyeld----klciKHGPSVAN 329
                         330       340       350       360       370       380       390       400
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
Feature 1                                                                                         
3DWB_A        293 YMIWNLVRKtssfldqrfqdade-----------------kfmevmygtkktslPRWKFCVSDTENnLGFALGPMFvk-- 353
1R1H_A        316 LMSWRFIMDlvsslsrtykesrn------------------afrkalygttsetATWRRCANYVNGnMENAVGRLYve-- 375
gi 34577157   474 YMITQLIFEdadflggvfkkaaeeanyvpya-qragrgiarvgqqlfrtadssgNANLPCISTIMHyMPYGPGYVYvknk 552
gi 34577159   441 YLLVHLIFEeadflggalkkmvqksdyapyalrrgkgvtrigqqlvrsyddsveDANIQCLNSMITyMPFGPGYVYvks- 519
gi 74966315   372 YMIAQLLADesdfinpatakvssdtnyihya--lrngrgikkigkreyrmadldGISEGCMDLLTAyMPYGTGYVYvks- 448
gi 74893537   408 YIIVHMLFEdaehlgdkylriakdadyvtya-qrkgvgitrsgrkysrvfdertDARMKCVDTITTyMPYGTGYVYvnsr 486
gi 198451121  337 YLAMLLLYRmdakl------------------------------------ksakYQKEHCLQVVQYsLPYLFDRLYrv-- 378
gi 24650765   338 YLAMRFLYRmddklk---------------------------------epkqpeDQKVNCLMIVQMtLPNLFNRLYma-- 382
gi 194746370 1005 YLAMLLLYRmdakl------------------------------------keekYHKDYCVSIVQSgFSFVLNKLYma-- 1046
gi 195444158  330 YLVMKLLYTmdadf------------------------------------kevkYQRDYCKGSILAsMPHLLGKLYfl-- 371
                         410       420       430       440       450       460       470       480
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
Feature 1                                                                                         
3DWB_A        354 atFAEDSKSIATEIILEIKKAFEeslstlkwMDEETRKSAKEKad-------aIYNMIGYPNFi-mDPKELDKVFndyta 425
1R1H_A        376 aaFAGESKHVVEDLIAQIREVFIqtlddltwMDAETKKRAEEKal-------aIKERIGYPDDivsNDNKLNNEYlelny 448
gi 34577157   553 gnERNQVAADISKQTELVLKNFMnmmsglkwMTSDSKRAAQMKakgmvknylwPEKLFGDFRDtskLDDYHNPDYgkiid 632
gi 34577159   520 rkNRDKVVQDIERQTELVFKNFVnmignlnwMTDASLERAMEKadkmvknygwPKDLFGDFRDsskIDAYHKKDYgriid 599
gi 74966315   449 ksERNKVQADVKDQTTLIINNFQgmidslnwMDTFSKNRAHNKsdslvknfgwPEAMFGDFNDfttVDAYNQDYAsiidl 528
gi 74893537   487 edRDQVVEDVKQQTELIMKTFLKkmlstlswMQGESYRRAEKKinemhrnygwPKKLFGDFKNfdtIDAYHRDDYysile 566
gi 198451121  379 eyFSEETSAEISGIIKELRKSFRlmlensewLDKETRTEALLKei-------sIEPRIGSFRDd-eLTERLVRAVnnlti 450
gi 24650765   383 ehFTDEKHSEISDMVTEMRKAQRqilesvewLDAETRAEALSKea-------gITPVIGSYKNe-eLSDTLIREInnlti 454
gi 194746370 1047 -hFKDRTRSEVSAIVQELRNSQKkalekvewLDPETRQAAQLKea-------sIEPVIGSYKNd-dVTIRLIQEIrsldl 1117
gi 195444158  372 eySIEDTSKEIQSIINELRKSFRvaienadfLDTRTRTEALKKes-------lIKSNIGCQQDd-aFTHLLIREMrnlsf 443
                         490       500       510       520       530       540       550       560
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
Feature 1                                                          ##                             
3DWB_A        426 ---vpdlyFENAMRFFNFSWRVTADqlr-----kaPNRDQWSMTPp-mVNAYYSptkNEIVFPAgILQAP-FYTRsspka 495
1R1H_A        449 ---kedeyFENIIQNLKFSQSKQLKklr-----ekVDKDEWISGAa-vVNAFYSsgrNQIVFPAgILQPP-FFSAqqsns 518
gi 34577157   633 l--ynqnyTHNYYKMRNMMIKGFANreslrlmkeePDRANFLMSPa-yVNAWYQperNSITFPYaYLNPP-FYNLkypqa 708
gi 34577159   600 l--ykqniTHNYYHIRRTMIKGYSNheslrlpteePKRDHFLMSPa-mVNAWYIperNSITFPYaFWNPP-YYSYeypqa 675
gi 74966315   529 ----ytkdKNDIYGIFAVLKKGMEVreffrimgepADRTNFLQSPa-mVNAWYQperNSITFPYaAWNPP-YYNLnypqa 602
gi 74893537   567 aynnktdkSTAFYTILNILRRGYENresfrrknetADRTNFLESPa-sVNAWYApelNSLTLPFgILTSP-HYDLqfpka 644
gi 198451121  451 vedsfaqtNINLKRFITYLRRFNGHhfs----elsNDTKPLELLWsmqVNAFYYnldNTIYVMAgILHPPaFHQLwp-ns 525
gi 24650765   455 vegsyaqsLINLRVLGTYLHRYAGLhad----elpKDTKPLTLLVgmqVNAFYYnldNSVYVMAgVLHPP-AYHRswpds 529
gi 194746370 1118 e--nasfsQSLIEQRKLITRLRRFNgfh----gepNDTKPLELYLgmqVNAFYYnldNSIYVMAgILHPP-AYHPdwpns 1190
gi 195444158  444 vdgsyaqnQINLKRFKVYIDRFNGHhne----elpEETVPSEALIcmqPNAFYYirdNSINVLSgSFHPP-VFHKywphs 518
                         570       580       590       600       610       620       630       640
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
Feature 1                 #  ##  #                                                                
3DWB_A        496 LNFGGIGVVVGHELTHAFDDQGReydkdg-------nlrpwWKNSSVEAFKRQTECMVeqysnysvn-----gepvngrh 563
1R1H_A        519 LNYGGIGMVIGHEITHGFDDNGRnfnkdg-------dlvdwWTQQSASNFKEQSQCMVyqygnfswdl--aggqhlngin 589
gi 34577157   709 FNYGGQGGTGGHEIVHGFDDEGVqfgpdgslskcmwhecgwMTSKSKDGFRDMAQCVVtqyntqccpeksgnilcangat 788
gi 34577159   676 YNYAGQGGTAGHELVHGFDDQGVqfdadgrlsgcswiecgwLEEKSKNGFGDMAQCVVtqystqccpqtggpphcangam 755
gi 74966315   603 YNFAGQGGTGGHELTHGYDDEGVqfgfngeltdcswnkcgwMDTNSSSGFIDMAQCVVtqfstqccpektgnihcangat 682
gi 74893537   645 FNFAGSGTVGGHELVHGFDDEGVqfdydgsladcsvyecgwLEQKGKNGFKDMAQCVVtqynaqccpakegnvhcangah 724
gi 198451121  526 LKYGTIGYLVGHELTHGFDTVGSmydgsg-------aqrnwWSKKSNAVFNERAECYAehysnylipe---inrkingnq 595
gi 24650765   530 LKFGTIGYLIGHELTHGFDTEGSsfdsag-------evrdwWSRKSEAVFQERAQCYVdyfnqylipe---inqtirgne 599
gi 194746370 1191 LKFGTLGYLVGHELTHGFDTVGSkfnseg-------emrnwWSKKSEAVFEERATCFVdhydrylipe---inrkingke 1260
gi 195444158  519 LKFGAMGYVIGHELNHGFDTVGSmvdsea-------evrdwWSNESRIAYKERTECFVkhfnnylipe---inrtingek 588
                         650       660       670       680       690       700       710       720
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
Feature 1            #                                                        ##                  
3DWB_A        564 TLGENIADNGGLKAAyRAYQNWvkkngae--------------hslptlgLTNNQLFFLGFAQVWCsvrtpessheglit 629
1R1H_A        590 TLGENIADNGGLGQAyRAYQNYikkngee--------------kllpgldLNHKQLFFLNFAQVWCgtyrpeyavnsikt 655
gi 34577157   789 TQGENIADLGGQQASyRAYREYiktkgkee------------krlpglerYTPNQIFWITYGFGWCrtqteenlikqilt 856
gi 34577159   756 PQGENIADLGGQLAAyLAYREYitkelgeee-----------krlpgleqYTPNQIFWITYGFSWCmsqtdsslirqllt 824
gi 74966315   683 TQGENIADLGGQQAAyRSYRQYvattrkgve----------edrlpglenYTPNQIFWITYGYSWCmkqsdanlvhqllt 752
gi 74893537   725 TQGENIADLGGLQASyNAYKEYikmkgaee------------mrlpglekFTPNQIFWISYGYSWCaketqsslvkrllt 792
gi 198451121  596 TKDENIADSGGLHEAlAAYRSYmkqqhqhlqqqdnethldknaeqmpgldLSPEQLFFLGFAQLWCnayeeehy-weels 674
gi 24650765   600 TRDENIADAGGLRAAlTGYRNHmkqlqrsgadget---lahkneqmpgldLSPEQLFFVGFAQLWCadyepehy-weelt 675
gi 194746370 1261 TQDENIADSGGLQGAlDAYRSHmkqlknrseedn----eilrseqmpgldLSPEQLFFLGFAQLWCadyeqehy-weelt 1335
gi 195444158  589 TKNENIADNGGLRQSlSAYRNFiknkinmpk-----------seqmpgmdHSPEQLFFLGFAQIYCsaykmtdy-wnels 656
                         730       740       750       760
                  ....*....|....*....|....*....|....*....|.
Feature 1           #     #                                
3DWB_A        630 dpHSPSRFRVIGSLSNsKEFSEHFRCppgsp--mnppHKCE 668
1R1H_A        656 dvHSPGNFRIIGTLQNsAEFSEAFHCrknsy--mnpeKKCR 694
gi 34577157   857 dpHSPSVCRVNQVVQDiPAFGKDFGCsvgqnmypapeQRCS 897
gi 34577159   825 dvHSPGSCRVNQVMQDiPEFARDFGCtmgqnmypepeQRCP 865
gi 74966315   753 npHSPAQCRTNQVMQDiPEFGKDFGCvrgspmypepsGRCK 793
gi 74893537   793 npHSPNSCRVNQVLQDiPSFAKDFQCalgqkmyppaeQRCK 833
gi 198451121  675 neHTIDKFRVLGAVTNnEDFAKVYNCpvgsp-mnphaERCR 714
gi 24650765   676 gaHTVDKYRVLGAVSNnDDFAEVYKCplgsp-mhpkaESCR 715
gi 194746370 1336 keHTIDKYRVLGAVSNnHDFSQVYNCpsgsp-mhpqeDTCR 1375
gi 195444158  657 dkHPTNKFRVIGALRNdEDFATAYNCplgsp-mnpktEKCH 696

| Disclaimer | Privacy statement | Accessibility |
NCBI Home NCBI Search NCBI SiteMap