Conserved Protein Domain Family
Cathepsin_D2

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cd05490: Cathepsin_D2 
Cathepsin_D2, pepsin family of proteinases.
Cathepsin D is the major aspartic proteinase of the lysosomal compartment where it functions in protein catabolism. It is a member of the pepsin family of proteinases. This enzyme is distinguished from other members of the pepsin family by two features that are characteristic of lysosomal hydrolases. First, mature Cathepsin D is found predominantly in a two-chain form due to a posttranslational cleavage event. Second, it contains phosphorylated, N-linked oligosaccharides that target the enzyme to lysosomes via mannose-6-phosphate receptors. Cathepsin D preferentially attacks peptide bonds flanked by bulky hydrophobic amino acids and its pH optimum is between pH 2.8 and 4.0. Two active site aspartic acid residues are essential for the catalytic activity of aspartic proteinases. Like other aspartic proteinases, Cathepsin D is a bilobed molecule; the two evolutionary related lobes are mostly made up of beta-sheets and flank a deep active site cleft. Each of the two related lobes contributes one active site aspartic acid residue and contains a single carbohydrate group. Cathepsin D is an essential enzyme. Mice deficient for proteinase cathepsin D, generated by gene targeting, develop normally during the first 2 weeks, stop thriving in the third week and die in a state of anorexia in the fourth week. The mice develop atrophy of ileal mucosa followed by other degradation of intestinal organs. In these knockout mice, lysosomal proteolysis was normal. These results suggest that vital functions of cathepsin D are exerted by limited proteolysis of proteins regulating cell growth and/or tissue homeostasis, while its contribution to bulk proteolysis in lysosomes appears to be non-critical. This family of aspartate proteases is classified by MEROPS as the peptidase family A1 (pepsin A, clan AA).
Statistics
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PSSM-Id: 133157
View PSSM: cd05490
Aligned: 7 rows
Threshold Bit Score: 643.381
Threshold Setting Gi: 118344572
Created: 8-Feb-2008
Updated: 17-Jan-2013
Structure
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Aligned Rows:
 
Feature 1:catalytic residue [active site]
Evidence:
  • Comment:The two ASPs at the active site plays key catalytic roles in the pepsin family and conserved for all family members.
  • Comment:Predicted based on homologous proteins woth structures.

Sequence Alignment
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Format: Row Display: Color Bits: Type Selection:
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
Feature 1                                #                                                       
gi 148229393  75 NYLDAQYYGEIGIGTPPQTFTVVFDTGSSNLWVPSVHCSMFDIACwmHHKYDSSKSSTYVKNGTEFAIQYGTGSLSGYLS 154
gi 13637914   53 NYMDAQYYGEIGIGTPPQCFTVVFDTGSANLWVPSIHCKLLDIACwtHRKYNSDKSSTYVKNGTTFDIHYGSGSLSGYLS 132
gi 461696     72 NYMDAQYYGEIGIGTPPQKFTVVFDTGSSNLWVPSVHCHLLDIACllHHKYDASKSSTYVENGTEFAIHYGTGSLSGFLS 151
gi 38571742   70 NYLDAQYYGEIGLGTPVQTFTVVFDTGSSNLWVPSVHCSLTDIACllHHKYNGGKSSTYVKNGTQFAIQYGSGSLSGYLS 149
gi 41053329   86 NFMDAQYYGMISIGTPPQDFSVLFDTGSSNLWVPSIHCAFLDIACwlHRRYNSKKSSTYVQNGTEFSIQYGRGSLSGFIS 165
gi 118344572  62 NIYDLQYFGKISIGTPPQEFTVLFDTGSSDLWVPSVYCSPLYLACglHRHYRSYRSSTYVQCDRGFFIEYQSGRLSGFVS 141
gi 115717     73 NYMDAQYYGEIGIGTPPQCFTVVFDTGSSNLWVPSIHCKLLDIACwiHHKYNSDKSSTYVKNGTSFDIHYGSGSLSGYLS 152
                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
Feature 1                                                                                        
gi 148229393 155 kDTVTIGnlg-----------ikEQLFGEAIKQPGVTFIAaKFDGILGMAYPIISVDgvsPVFDNIMAQKLVESNVFSFY 223
gi 13637914  133 qDTVSVPcnpssss--pggvtvqRQTFGEAIKQPGVVFIAaKFDGILGMAYPRISVNnvlPVFDNLMQQKLVDKNVFSFF 210
gi 461696    152 qDTVTLGnlk-----------ikNQIFGEAVKQPGITFIAaKFDGILGMAFPRISVDkvtPFFDNVMQQKLIEKNIFSFY 220
gi 38571742  150 qDTCTIGdia-----------veKQIFGEAIKQPGVAFIAaKFDGILGMAYPRIAVDgvpPVFDMMMSQKKVEKNVFSFY 218
gi 41053329  166 qDTVNLAgln-----------vtGQQFAEAVKQPGIVFAVaRFDGVLGMAYPAISVDrvtPVFDTAMAAKILPQNIFSFY 234
gi 118344572 142 kDTLSIGglq-----------vpGQLFGEAVRQPGETFIYtQFDGILGMAYPSISTIa--PVFDRIMAAKLLPQNVFSFY 208
gi 115717    153 qDTVSVPcqsassasalggvkveRQVFGEATKQPGITFIAaKFDGILGMAYPRISVNnvlPVFDNLMQQKLVDQNIFSFY 232
                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
Feature 1                                                                      #                 
gi 148229393 224 LNRNPdtqpGGELLLGGTDpkYYTGDFHYLNVTRKaYWQIHMdqlgvgdqLTLCKGGCEAIVDTGTSLITGPLEEVTALQ 303
gi 13637914  211 LNRDPkaqpGGELMLGGTDskYYRGSLMFHNVTRQaYWQIHMdqldvgssLTVCKGGCEAIVDTGTSLIVGPVEEVRELQ 290
gi 461696    221 LNRDPtaqpGGELLLGGTDpkYYSGDFSWVNVTRKaYWQVHMdsvdvangLTLCKGGCEAIVDTGTSLITGPTKEVKELQ 300
gi 38571742  219 LNRNPdtqpGGELLLGGTDpkYYTGDFNYVDISRQaYWQIHMdgmsigsgLSLCKGGCEAIVDTGTSLITGPAAEVKALQ 298
gi 41053329  235 INRDPagdvGGELMLGGFDqqYFNGDLHYVNVTRKaYWQIKMdevqvgstLTLCKSGCQAIVDTGTSMITGPVQEVRALQ 314
gi 118344572 209 LNRDPeaaiGGQLILGGLNpeHYAGELHYVNVTRKaYWQIEVnrinvgdqLSLCKPSCQTIVDTGTSLITGPSEEIRALH 288
gi 115717    233 LSRDPdaqpGGELMLGGTDskYYKGSLSYLNVTRKaYWQVHLdqvevasgLTLCKEGCEAIVDTGTSLMVGPVDEVRELQ 312
                        250       260       270       280       290       300       310       320
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
Feature 1                                                                                        
gi 148229393 304 KAIGAVPLIQGqymVQCDKIPTLPVISLTLGGQVYTLTGEQYIMKVSqrGSTICLSGFMGLNIPPPAGPLWILGDVFIGQ 383
gi 13637914  291 KAIGAVPLIQGeymIPCEKVSSLPEVTVKLGGKDYALSPEDYALKVSqaETTVCLSGFMGMDIPPPGGPLWILGDVFIGR 370
gi 461696    301 TAIGAKPLIKGqyvISCDKISSLPVVTLMLGGKPYQLTGEQYVFKVSaqGETICLSGFSGLDVPPPGGPLWILGDVFIGP 380
gi 38571742  299 KAIGAIPLMQGeymVDCKKVPTLPTISFSLGGKVYSLTGEQYILKESqgGHDICLSGFMGLDIPPPAGPLWILGDVFIGQ 378
gi 41053329  315 KAIGAIPLLMGeywIDCKKIPTLPVVSFSLGGKMFNLTGQEYVMKMShmGMNVCLSGFMAMDIPPPAGPLWILGDVFIGR 394
gi 118344572 289 NAIPGMSRQKDeniIDCEQIPSMPVISFNIGGKLFPLNPEDYIWKEMdrGTAFCQSRFMALDMGPPAAPLWNLGDVFIMK 368
gi 115717    313 KAIGAVPLIQGeymIPCEKVSTLPAITLKLGGKGYKLSPEDYTLKVSqaGKTLCLSGFMGMDIPPPSGPLWILGDVFIGR 392
                        330
                 ....*....|....*.
Feature 1                        
gi 148229393 384 YYSVFDRAnDRVGFAK 399
gi 13637914  371 YYTVFDRDqNRVGLAE 386
gi 461696    381 YYTVFDRDnDSVGFAK 396
gi 38571742  379 YYTVFDREnNRVGFAK 394
gi 41053329  395 YYTVFDRDqDRVGFAP 410
gi 118344572 369 YYTVFDRDaDRVGFAL 384
gi 115717    393 YYTVFDRDnNRVGFAE 408

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