4JKV


Conserved Protein Domain Family
7tmF_Frizzled_SMO

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cd13951: 7tmF_Frizzled_SMO 
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class F frizzled/smoothened family, member of the 7-transmembrane G protein-coupled receptor superfamily
The class F G protein-coupled receptors includes the frizzled (FZD) family of seven-transmembrane proteins consisting of 10 isoforms (FZD1-10) in mammals. The FZDs are activated by the wingless/int-1 (WNT) family of secreted lipoglycoproteins and preferentially couple to stimulatory G proteins of the Gs family, which activate adenylate cyclase, but can also couple to G proteins of the Gi/Gq families. In the WNT/beta-catenin signaling pathway, the WNT ligand binds to FZD and a lipoprotein receptor-related protein (LRP) co-receptor. This leads to the stabilization and translocation of beta-catenin to the nucleus, where it induces the activation of TCF/LEF family transcription factors. The conserved cytoplasmic motif of FZD, Lys-Thr-X-X-X-Trp, is required for activation of the WNT/beta-catenin pathway, and for membrane localization and phosphorylation of Dsh (dishevelled) protein, a key component of the WNT pathway that relays the WNT signals from the activated receptor to downstream effector proteins. Also included in the class F family is the closely related smoothened (SMO), which is a transmembrane G protein-coupled receptor that acts as the transducer of the hedgehog (HH) signaling pathway. SMO is activated by the hedgehog (HH) family of proteins acting on the 12-transmembrane domain receptor patched (PTCH), which constitutively inhibits SMO. Thus, in the absence of HH proteins, PTCH inhibits SMO signaling. On the other hand, binding of HH to the PTCH receptor activates its internalization and degradation, thereby releasing the PTCH inhibition of SMO. This allows SMO to trigger intracellular signaling and the subsequent activation of the Gli family of zinc finger transcriptional factors and induction of HH target gene expression (PTCH, Gli1, cyclin, Bcl-2, etc). The WNT and HH signaling pathways play critical roles in many developmental processes, such as cell-fate determination, cell proliferation, neural patterning, stem cell renewal, tissue homeostasis and repair, and tumorigenesis, among many others.
Statistics
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PSSM-Id: 320089
View PSSM: cd13951
Aligned: 20 rows
Threshold Bit Score: 284.597
Threshold Setting Gi: 62122563
Created: 21-Dec-2011
Updated: 26-Jul-2017
Structure
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Program:
Drawing:
Aligned Rows:
  next features
Conserved site includes 14 residues -Click on image for an interactive view with Cn3D
Feature 1:ligand binding site [chemical binding site]
Evidence:
  • Structure:4JKV: Human smoothened receptor binds an antitumor agent (LY2940680), contacts at 4A.
    View structure with Cn3D

Sequence Alignment
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Format: Row Display: Color Bits: Type Selection:
                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
Feature 1         #        #                                                    #                
4JKV_A       140 PLFTEAEHQDMHSYIAAFGAVTGLCTLFTLATFVADWRnsn--rypAVILFYVNACFFVGSIGWLAQFMDgarREIVCRa 217
gi 20454884  225 AFHTSSQKKTSETLILGLSAVCFVLTLFALVTFWAEPTrfg---ypERPVLFLCLCYNLFSVCYLERIVFh--NQARMHd 299
gi 24640330  222 ILFTPAEKHLAEIWVSTWAYAALGLALVATVCLLASDGsrlasakwSRLLSPLIWCHNMVTLGWAVRFMVg-rTGTACGt 300
gi 386118343 245 GIFTTQQKQLAERWISALTCICGILSVAAILCVLANYNetc---fpERTIFFIAVCYFFYVVGYMIRIVYs-rEGVTCQk 320
gi 308194275 188 SYYTDGMKSFTKGWIATWSTLCFLSTSLTLLTFIIKPSrfe---ypWRPIIFLALCFNIHSLGYFFSLALg-rGIITCPg 263
gi 38524368  183 SYFTDSAKSFAQGWLAFWALICFISTTLTIATFVLDPSrfq---ypWRPVVYLSLSFNLHSLTHFFSKGLg-rDLVTCPg 258
gi 190580481  24 GLFTSKEKKRMNTYMALLSALTFSFTLIAILTAAIRPQrfq---ypERILIFMSICYNIYALVHLLRVFLr-yETVACGk 99
gi 449534511 258 GLFTFEQKESMEKWISALSCCCCLLCFLAMFVTFGEYKktl---ypQRTILFITISYVFYSIAHIVRIVSs-rEAVSCQe 333
gi 62122563  248 PFIENNRYYLISLWLSISVGLIFICCISSLLTFFLNRLeli--qppHRFVAYICCCQIGMSIGFIIRLVAg-hYKTVCFq 324
gi 308535440 170 ILFSVSEQNTTRVWIMAWSSIALSLSFVMLFVVTSHGKvn----kpENIIVIICFCFRFQAAGFLLSVMVp-eSPFKCSi 244
                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
Feature 1                                                                                        
4JKV_A       218 dgtmrl-------geptsnETLSCVIIFVIVYYALMAGVVWFVVLTYAWHTSFKALGTt--------------------- 269
gi 20454884  300 velqgr------lmrpgclLTPPCLASYITTSYLSLCAASWWLIFALCFYLSSHKKWSs--------------------- 352
gi 24640330  301 dpqapne----slltvdglSNASCASVFLMRYYFGMAACAWWAVLCLGWHRDIRRHSPdskghvvipsnfggspakrnsa 376
gi 386118343 321 engqhy-------llvdgsGNISCAATFLLVYCFSMVQSIWWVILCLTWFLSAGMRWAt--------------------- 372
gi 308194275 264 nnyiss-------sskwswSHIPCLLNFGLLYYSMVSAFLWWLALTLSWFLSAVFKWSn--------------------- 315
gi 38524368  259 nqfvqt-------sitwtwGHTPCILVFGLLHETMMTAFLWWLMLSFSWFLASAFSWSs--------------------- 310
gi 190580481 100 ldssnril--tkmtnssilSHVPCTVIFIMLYYFDLVASIWLVVLTLLWYLSAKKKWCs--------------------- 156
gi 449534511 334 eegrsy-------liwdgsGNIPCAATFLFIYCSYMAQNIWWVILTLTWFLCSGLKWKq--------------------- 385
gi 62122563  325 pdykpiheslllmlrfqnsAPSVCSISFLFTYFFFFASVLWWWLLCLTWFFSDGLGWSs--------------------- 383
gi 308535440 245 pekpgdp-----iylklnsPSPTCYLSFTATYFSGLAANLWWVTLNLLWFLMLGMNWSs--------------------- 298
                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
Feature 1                                            #    # #            #                       
4JKV_A       270 --yQPLSGKTSYFHLLTWSLPFVLTVAILAVAqVDGDSVSGICFVGy----kNYRYRAGFVLAPIGLVLIVGGYFLIRGV 343
gi 20454884  353 ---EALEKRSGLFHVLAWVPPLAPPIAALLLEkVRPSELTGMCYAPgf---vELPALVLLLLGLYFTLRASRSLLSLQQQ 426
gi 24640330  377 ktaQQDLTQNNFVCFVAWGLPAFQTSAVIVARfVDADELLGACFVGn----qSDKALQILVATPVFCYWIFGSMNLISGY 452
gi 386118343 373 ---EAIRSKSFMFHSLAWGIPCCKTVIVLVWRkIDVNELTGICSIGnr--yeNLRALRWLILGPLFVYLIMATMFLLFGL 447
gi 308194275 316 ---ESVGRLAPFFHVTAWVVPLLMMISLVAAQvISADELTGTCFIVrdesnaTLFGLLIGVIIPLLLFLSIGLLFLIIGL 392
gi 38524368  311 ---EAVSHLAPFYHVIAWVLPLVLTIILVATRvVGADELTATCFIVrdendmSFYALLLGVIIPLVACLITGVVFLVIGF 387
gi 190580481 157 ---EIITGYAVYYHTLSWIIPAVPVAVIILWKkVSADELTGLCYISshlatqKGFYLIGFVILPHSLCLLLASVFMIVFY 233
gi 449534511 386 ---ATIQSKSFYFHLVAWGVPCAKTLVIFVARkIDVNELTGMCTIGnr--yeNLSSLSGFVLGPLFTYLITGTIFLIFGV 460
gi 62122563  384 ---SMIDKYSQLYHFIAWFFPGIFSMLALTMSaVDGDPVTGLCLVGn----iNRQHLITFLLAPLCVFTCSGLFFLACGF 456
gi 308535440 299 --sGSIFKVFRYLHLVIGGLAGGLTITVLTVGaVEGEGLSGGCVAGg----vHPENLATYDLTPNCVLLCIGGVVLLCGT 372
                        250       260       270       280       290       300       310       320
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
Feature 1                                                                                #   ##  
4JKV_A       344 MTLFSIKSNHpgll-------------------sekaASKINETMLRLGIFGFLAFGFVLITFSCHFYDFFNQAe-WERs 403
gi 20454884  427 LQPTLAHHRFgq------------------------iRKRFVLFSLLYFAPTTAGVVAALCERYADSVPSCSTPddCLSp 482
gi 24640330  453 LVHCRTKEILrnsnal---------------svqqqlQQLSAHSSSGIGIFLFIYGLACAMLLLAVIYEFANIDv-WLGs 516
gi 386118343 448 ICLFRLPDPNenq---------------------lmeRKKNQYLLLPIGSYAALHTLFMTFILASYFYEYVNKGp-WYNd 505
gi 308194275 393 ISVFRIRRFLhnkg-------------------rqkeSIVLEKLMFRIGIFVAVYVLPAGAVISCYIYELAKVPd-WVTl 452
gi 38524368  388 VSLFRIHSIMrhsg-------------------kateSSILEKLMIRIGIFVVVFILPAVIVVGCFMYELISRPf-WTPi 447
gi 190580481 234 VSTRKIKAQLaqnta------------------akasMVKLSRFRGRVLTFFIFYWLLASIIIGCYCYEYTQGPy-WQPl 294
gi 449534511 461 LVLFKLPANTlk-----------------------nrSVKIELRSASDALYATLHAALSIFVLSSYFYEYFEKYa-WYNd 516
gi 62122563  457 LSVTKCDQSSshrsklsvpvsprtistdtsvesaassLPKITTSSITKCFYGFLGLICSIPLCLTTGSIVYEMR--WRSh 534
gi 308535440 373 YTLVKISRIEgyt----------------------ltHDIPVQRLKNTAIFSYFYLLISLVKILCQFYELAYRSe-WYRn 429
                        330       340       350       360       370       380       390       400
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
Feature 1                                                      #    #  ##                        
4JKV_A       404 frdyvlcqanvti-----------------glptkqpipdceikNRPSLLVEKINLFAMFGTGIAMSTWVWTKATLLIWR 466
gi 20454884  483 --------------------------------------------TPLSAWPALVRIFFQLVGGTLTGLWVWSRKTCESYR 518
gi 24640330  517 g------------------------------------------dTNTPLWPFLLRAFMELMLGICCFAWVLGPSISTLYK 554
gi 386118343 506 p-----------------------------------------ksTGPSFAVFLTRIISDFSIGISASIWLLLIHGPRLHR 544
gi 308194275 453 neaes---------------------------------csdggcQKASPIVFIIRIFMFLMIGILTGVWIWSKKTLDSWR 499
gi 38524368  448 sep-------------------------------------cndcVLGNPAVFMTRLFMFLLTGILTGVWIWSKKTLLSWR 490
gi 190580481 295 hrnqsrfnq-------------------------fpcekrqnihSDVHISVLAVKLLAQLLRGIVVSFWIASRKTVNEWE 349
gi 449534511 517 p-----------------------------------------nsSGPNYNIFLMRVIAVFAIGICAALLLISLHLPAFYK 555
gi 62122563  535 wevlttcsc-------------------------lnemesnsylSTPSILLYILKYSGFFAIGIICGPWIWPMQTFNTWL 589
gi 308535440 430 cdpnsrtdfanlevnnltdspggfsfanhtfsnstsgsletdspCGPEVRIFIAKYTCYLLLPILVSVHLKNTVSILDII 509

                 ....
Feature 1            
4JKV_A       467 RTWC 470
gi 20454884  519 NRLG 522
gi 24640330  555 RQVS 558
gi 386118343 545 RMKV 548
gi 308194275 500 SLGN 503
gi 38524368  491 NLPQ 494
gi 190580481 350 NIFR 353
gi 449534511 556 HLKA 559
gi 62122563  590 EPII 593
gi 308535440 510 KRLV 513

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