Cysteine-rich domain of the secreted frizzled-related protein 1 (SFRP1), a regulator of Wnt activity; The cysteine-rich domain (CRD) is an essential part of the secreted frizzled-related protein 1 (SFRP1), which regulates the activity of Wnt proteins, key players in a number of fundamental cellular processes such as embryogenesis and postnatal development. SFRPs antagonize the activation of Wnt signaling by binding to the CRDs domains of frizzled (Fz) proteins, thereby preventing Wnt proteins from binding to these receptors. SFRPs are also known to have functions unrelated to Wnt, as enhancers of procollagen cleavage by the TLD proteinases. SFRPs and Fz proteins both contain CRD domains, but SFRPs lack the seven-pass transmembrane domain which is an integral part of Fzs. SFRP1 is expressed in many tissues and is involved in the regulation of Wnt signaling in osteoblasts, leading to enhanced trabecular bone formation in adults; it has also been shown to control the growth of retinal ganglion cell axons and the elongation of the antero-posterior axis.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 989973164  44 YTKPPQCVDIPADLRLCHNVGYKKMVLPNLLEHETMAEVKQQASSWVPLLNKNCHIGTQVFLCSLFAPVCLDRPIYPCRW 123
Cdd:cd07443    1 YTKPPQCVDIPADLRLCHNVGYKKMVLPNLLDHETMAEVKQQASSWVPLLNKNCHKGTQVFLCSLFAPVCLDRPVYPCRW 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....
gi 989973164 124 LCEAVRDSCEPVMQFFGFYWPEMLKCDKFPEGDVCIAMTPPNAT 167
Cdd:cd07443   81 LCEAVRDSCEPVMQFFGFYWPEMLKCDKFPEGEVCIAMTPPNAT 124

Cysteine-rich domain of the secreted frizzled-related protein 1 (SFRP1), a regulator of Wnt activity; The cysteine-rich domain (CRD) is an essential part of the secreted frizzled-related protein 1 (SFRP1), which regulates the activity of Wnt proteins, key players in a number of fundamental cellular processes such as embryogenesis and postnatal development. SFRPs antagonize the activation of Wnt signaling by binding to the CRDs domains of frizzled (Fz) proteins, thereby preventing Wnt proteins from binding to these receptors. SFRPs are also known to have functions unrelated to Wnt, as enhancers of procollagen cleavage by the TLD proteinases. SFRPs and Fz proteins both contain CRD domains, but SFRPs lack the seven-pass transmembrane domain which is an integral part of Fzs. SFRP1 is expressed in many tissues and is involved in the regulation of Wnt signaling in osteoblasts, leading to enhanced trabecular bone formation in adults; it has also been shown to control the growth of retinal ganglion cell axons and the elongation of the antero-posterior axis.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 989973164  44 YTKPPQCVDIPADLRLCHNVGYKKMVLPNLLEHETMAEVKQQASSWVPLLNKNCHIGTQVFLCSLFAPVCLDRPIYPCRW 123
Cdd:cd07443    1 YTKPPQCVDIPADLRLCHNVGYKKMVLPNLLDHETMAEVKQQASSWVPLLNKNCHKGTQVFLCSLFAPVCLDRPVYPCRW 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....
gi 989973164 124 LCEAVRDSCEPVMQFFGFYWPEMLKCDKFPEGDVCIAMTPPNAT 167
Cdd:cd07443   81 LCEAVRDSCEPVMQFFGFYWPEMLKCDKFPEGEVCIAMTPPNAT 124

NTR domain, Secreted frizzled-related protein (Sfrp) 1-like subfamily; composed of proteins similar to human Sfrp1, Sfrp2 and Sfrp5. Sfrps are soluble proteins containing an NTR domain C-terminal to a cysteine-rich Frizzled domain. They show diverse functions and are thought to work in Wnt signaling indirectly, as modulators or antagonists by binding Wnt ligands, and directly, via the Wnt receptor, Frizzled. They participate in regulating the patterning along the anteroposterior axis in vertebrates. Human Sfrp1 has been found frequently to be downregulated in breast cancer and is associated with disease progression and poor prognosis.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 989973164 175 TTVCPPCDNELKS-EAIIEHLCASEFALRMKIKEVKKENGDKKIVPKKKKPL-KLGPIKKKELKKLVLYLKNGADCPCHQ 252
Cdd:cd03580    1 PKVCPPCENEEESaKTLLDNFCASDFALKVKIKEISYENGDRKVIGEKKKEIlKQGPLKKKDLKKLVLWLKNGANCPCPQ 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*.
gi 989973164 253 LDNLSHHFLIMGRKVKSQYLLTAIHKWDKKNKEFKNFMKKMKNHEC 298
Cdd:cd03580   81 LDNLNGVYLVMGRKVDGKLLLTSIYKWQKKNKEFKRAVRKWKKHKC 126

Netrin C-terminal Domain;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 989973164   191 IEHLCASE--FALRMKIKEVKKENGDKKIVPKKKKPLKLGPIKKKELKKLVLYLKNGADCPCHQLDNLSHHFLIMGRKV- 267
Cdd:smart00643   1 LEKACKSDvdYVYKVKVLSVEEEGGFDKYTVKILEVIKSGTDELVRGKNKLRVFISRASCRCPLLLKLGKSYLIMGKSGd 80

                           90       100       110
                   ....*....|....*....|....*....|....
gi 989973164   268 ------KSQYLLTA---IHKWDKKNK-EFKNFMK 291
Cdd:smart00643  81 lwdakgRGQYVLGKnswVEEWPTEEEcRLRRLQK 114

Cysteine-rich domain of the secreted frizzled-related protein 1 (SFRP1), a regulator of Wnt activity; The cysteine-rich domain (CRD) is an essential part of the secreted frizzled-related protein 1 (SFRP1), which regulates the activity of Wnt proteins, key players in a number of fundamental cellular processes such as embryogenesis and postnatal development. SFRPs antagonize the activation of Wnt signaling by binding to the CRDs domains of frizzled (Fz) proteins, thereby preventing Wnt proteins from binding to these receptors. SFRPs are also known to have functions unrelated to Wnt, as enhancers of procollagen cleavage by the TLD proteinases. SFRPs and Fz proteins both contain CRD domains, but SFRPs lack the seven-pass transmembrane domain which is an integral part of Fzs. SFRP1 is expressed in many tissues and is involved in the regulation of Wnt signaling in osteoblasts, leading to enhanced trabecular bone formation in adults; it has also been shown to control the growth of retinal ganglion cell axons and the elongation of the antero-posterior axis.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 989973164  44 YTKPPQCVDIPADLRLCHNVGYKKMVLPNLLEHETMAEVKQQASSWVPLLNKNCHIGTQVFLCSLFAPVCLDRPIYPCRW 123
Cdd:cd07443    1 YTKPPQCVDIPADLRLCHNVGYKKMVLPNLLDHETMAEVKQQASSWVPLLNKNCHKGTQVFLCSLFAPVCLDRPVYPCRW 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....
gi 989973164 124 LCEAVRDSCEPVMQFFGFYWPEMLKCDKFPEGDVCIAMTPPNAT 167
Cdd:cd07443   81 LCEAVRDSCEPVMQFFGFYWPEMLKCDKFPEGEVCIAMTPPNAT 124

Cysteine-rich domain of the crescent protein; The cysteine-rich domain (CRD) is an essential part of the crescent protein, a member of the secreted frizzled-related protein (SFRP) family, which regulates convergent extension movements (CEMs) during gastrulation and neurulation. Xenopus laevis crescent efficiently forms inhibitory complexes with Wnt5a and Wnt11, but this effect is cancelled in the presence of another member of the SFRP family, Frzb1. A potential role for Crescent in head formation is to regulate a non-canonical Wnt pathway positively in the adjacent posterior mesoderm, and negatively in the overlying anterior neuroectoderm.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 989973164  50 CVDIPADLRLCHNVGYKKMVLPNLLEHETMAEVKQQASSWVPLLNKNCHIGTQVFLCSLFAPVCLDRPIYPCRWLCEAVR 129
Cdd:cd07453    3 CMRIPKSMALCYDIGYSEMRIPNLLEHETMAEVIQQSSSWLPLLARECHPDARIFLCSLFAPICWDRPIYPCRSLCEAVR 82

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 989973164 130 DSCEPVMQFFGFYWPEMLKCDKFPEG-DVCIAmtpPNATEASKPQGTTVCPPCDNE 184
Cdd:cd07453   83 SSCAPLMACYGYPWPEILHCDKFPVDhDLCIS---PQFIDTLSPERVKPRASCEDC 135

Frizzled; Drosophila melanogaster frizzled mediates signalling that polarises a precursor cell along the anteroposterior axis. Homologues of the N-terminal region of frizzled exist either as transmembrane or secreted molecules. Frizzled homologues are reported to be receptors for the Wnt growth factors. (Not yet in MEDLINE: the FRI domain occurs in several receptor tyrosine kinases [Xu, Y.K. and Nusse, Curr. Biol. 8 R405-R406 (1998); Masiakowski, P. and Yanopoulos, G.D., Curr. Biol. 8, R407 (1998)].

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 989973164    53 IPADLRLCHNVGYKKMVLPNLLEHETMAEVKQQASSWVPLLNKNCHIGTQVFLCSLFAPVCLDR--PIYPCRWLCEAVRD 130
Cdd:smart00063   2 EPITIPLCKDLGYNLTSMPNLLGHTTQEEAGLELEQFHPLLNVQCSPDLRFFLCSVYAPICTEDlrPILPCRSLCEAARE 81

                           90       100       110
                   ....*....|....*....|....*....|..
gi 989973164   131 SCEPVMQFFGFYWPEMLKCDKFP-EGDVCIAM 161
Cdd:smart00063  82 GCEPLMEKFGFPWPEFLRCDRFPvQEELCMDP 113

Cysteine-rich domain of the sizzled protein; The cysteine-rich domain (CRD) is an essential part of the sizzled protein, which regulates bone morphogenetic protein (Bmp) signaling by stabilizing chordin, and plays a critical role in the patterning of vertebrate and invertebrate embryos. Sizzled also functions in the ventral region as a Wnt inhibitor and modulates canonical Wnt signaling. Sizzled proteins belong to the secreted frizzled-related protein family (SFRP), and have be identified in the genomes of birds, fishes and frogs, but not mammals.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 989973164  49 QCVDIPADLRLCHNVGYKKMVLPNLLEHETMAEVKQQASSWVPLLNKNCHIGTQVFLCSLFAPVCLDRPIYPCRWLCEAV 128
Cdd:cd07452    8 KCVPIPPEMSMCQDVGYSEMRLPNLLGHTSMAEVVPKSADWQTLLHTGCHPHARTFLCSLFAPVCLDTFIQPCRSMCVAV 87

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....
gi 989973164 129 RDSCEPVMQFFGFYWPEMLKCDKFPEG-DVCIAMTPPNATEASKPQGTTVCPPC 181
Cdd:cd07452   88 RDSCAPVLACHGHSWPESLDCDRFPAGeDMCLASLSKEYQYFYKEFPKPACQSC 141

Cysteine-rich Wnt-binding domain of the frizzled 4 (Fz4) receptor; The cysteine-rich domain (CRD) is an essential extracellular portion of the frizzled 4 (Fz4) receptor, and is required for binding Wnt proteins, which play fundamental roles in many aspects of early development, such as cell and tissue polarity, neural synapse formation, and the regulation of proliferation. Fz proteins serve as Wnt receptors for multiple signal transduction pathways, including both beta-catenin dependent and -independent cellular signaling, as well as the planar cell polarity pathway and the Ca(2+) modulating signaling pathway. CRD containing Fzs have been found in diverse species from amoebas to mammals. 10 different frizzled proteins are found in vertebrata. Frizzled 4 (Fz4) activates the Ca(2+)/calmodulin-dependent protein kinase II and protein kinase C of the Wnt/Ca(2+) signaling pathway during retinal angiogenesis. Mutations in Fz4 lead to familial exudative vitreoretinopathy (FEVR), a hereditary ocular disorder characterized by failure of the peripheral retinal vascularization. In addition, the interplay between Fz4 and norrin as a receptor-ligand pair plays an important role in vascular development in the retina and inner ear in a Wnt-independent manner.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 989973164  54 PADLRLCHNVGYKKMVLPNLLEHETMAEVKQQASSWVPLLNKNCHIGTQVFLCSLFAPVC---LDRPIYPCRWLCEAVRD 130
Cdd:cd07448    6 PIRIEMCQGLGYNVTRMPNLVGHELQTDAELQLQTFTPLIQYGCSSQLKFFLCSVYVPMCtekVPVPIGPCRPLCLSVKK 85

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|...
gi 989973164 131 SCEPVMQFFGFYWPEMLKCDKFP----EGDVCiaMTPPNATEA 169
Cdd:cd07448   86 RCLPVLKEFGFPWPEALNCSKFPpqnnHNHMC--MEGPGDEEV 126

Cysteine-rich Wnt-binding domain (CRD) of receptors similar to frizzled 1; The cysteine-rich domain (CRD) is an essential extracellular portion of the frizzled 1 (Fz1), frizzled 2 (Fz2), and frizzled 7 (Fz7) receptors, and similar proteins. This domain is required for binding Wnt proteins, which play fundamental roles in many aspects of early development, such as cell and tissue polarity, neural synapse formation, and the regulation of proliferation. Fz proteins serve as Wnt receptors for multiple signal transduction pathways, including both beta-catenin dependent and -independent cellular signaling, as well as the planar cell polarity pathway and Ca(2+) modulating signaling pathway. The CRD domain is well conserved in metazoans - 10 frizzled proteins have been identified in mammals, 4 in Drosophila and 3 in Caenorhabditis elegans. Very little is known about the mechanism by which CRD domains interact with their ligands. The domain contains 10 conserved cysteines.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 989973164  54 PADLRLCHNVGYKKMVLPNLLEHETMAEVKQQASSWVPLLNKNCHIGTQVFLCSLFAPVC--LDRPIYPCRWLCEAVRDS 131
Cdd:cd07458    5 PITIPLCTDIPYNMTIFPNLLGHTKQEDAGLEVHQFYPLVKVQCSPDLKFFLCSVYAPVCtvLERPIPPCRSLCESARQG 84

                         90       100       110
                 ....*....|....*....|....*....|..
gi 989973164 132 CEPVMQFFGFYWPEMLKCDKFPE---GDVCIA 160
Cdd:cd07458   85 CEALMNKFGFQWPESLDCEKFPVhgaGDLCVG 116

Cysteine-rich Wnt-binding domain (CRD) of the frizzled 9 (Fz9) receptor; The cysteine-rich domain (CRD) is an essential extracellular portion of the frizzled 9 (Fz9) receptor, and is required for binding Wnt proteins, which play fundamental roles in many aspects of early development, such as cell and tissue polarity, neural synapse formation, and the regulation of proliferation. Fz proteins serve as Wnt receptors for multiple signal transduction pathways, including both beta-catenin dependent and -independent cellular signaling, as well as the planar cell polarity pathway and Ca(2+) modulating signaling pathway. CRD containing Fzs have been found in diverse species from amoebas to mammals. 10 different frizzled proteins are found in vertebrata. Fz9 may play a signaling role in lymphoid development and maturation, particularly at points where B cells undergo self-renewal prior to further differentiation.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 989973164  47 PPQCVDIPadlrLCHNVGYKKMVLPNLLEHETMAEVKQQASSWVPLLNKNCHIGTQVFLCSLFAPVCLDR---PIYPCRW 123
Cdd:cd07463    4 KCQPVVIP----MCRGIGYNLTRMPNFLGHDSQREAAIKLNEFAPLVEYGCHVHLRFFLCSLYAPMCTDQvstSIPACRP 79

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|...
gi 989973164 124 LCEAVRDSCEPVMQFFGFYWPEMLKCDKFPegdvciAMTPPNATEASKPQGTT 176
Cdd:cd07463   80 MCEQARQKCSPIMEQFNFGWPESLDCSRLP------TRNDPNALCMEAPENAT 126

Cysteine-rich Wnt-binding domain (CRD) of the frizzled 7 (Fz7) receptor; The cysteine-rich domain (CRD) is an essential extracellular portion of the frizzled 7 (Fz7) receptor, and is required for binding Wnt proteins, which play fundamental roles in many aspects of early development, such as cell and tissue polarity, neural synapse formation, and the regulation of proliferation. Fz proteins serve as Wnt receptors for multiple signal transduction pathways, including both beta-catenin dependent and -independent cellular signaling, as well as the planar cell polarity pathway and Ca(2+) modulating signaling pathway. CRD containing Fzs have been found in diverse species from amoebas to mammals. 10 different frizzled proteins are found in vertebrata. Xenopus Fz7 is important in Wnt/beta-catenin signaling pathways controlling the transcriptional activation of target genes Siamois and Xnr3 in the animal caps of late blastula.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 989973164  54 PADLRLCHNVGYKKMVLPNLLEHETMAEVKQQASSWVPLLNKNCHIGTQVFLCSLFAPVC--LDRPIYPCRWLCEAVRDS 131
Cdd:cd07466    7 PISIPLCTDIAYNQTIMPNLLGHTNQEDAGLEVHQFYPLVKVQCSPELKFFLCSMYAPVCtvLEQAIPPCRSLCERARQG 86

                         90       100       110
                 ....*....|....*....|....*....|..
gi 989973164 132 CEPVMQFFGFYWPEMLKCDKFP---EGDVCIA 160
Cdd:cd07466   87 CEALMNKFGFQWPERLRCENFPvhgAGEICVG 118

Cysteine-rich Wnt-binding domain (CRD) of the frizzled 1 (Fz1) receptor; The cysteine-rich domain (CRD) is an essential extracellular portion of the frizzled 1 (Fz1) receptor, and is required for binding Wnt proteins, which play fundamental roles in many aspects of early development, such as cell and tissue polarity, neural synapse formation, and the regulation of proliferation. Fz proteins serve as Wnt receptors for multiple signal transduction pathways, including both beta-catenin dependent and -independent cellular signaling, as well as the planar cell polarity pathway and Ca(2+) modulating signaling pathway. CRD containing Fzs have been found in diverse species from amoebas to mammals. 10 different frizzled proteins are found in vertebrata.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 989973164  54 PADLRLCHNVGYKKMVLPNLLEHETMAEVKQQASSWVPLLNKNCHIGTQVFLCSLFAPVC--LDRPIYPCRWLCEAVRDS 131
Cdd:cd07465    7 PISIPLCTDIAYNQTIMPNLLGHTNQEDAGLEVHQFYPLVKVQCSAELKFFLCSMYAPVCtvLEQALPPCRSLCERARQG 86

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....
gi 989973164 132 CEPVMQFFGFYWPEMLKCDKFP---EGDVCIAMtppNATEASKP 172
Cdd:cd07465   87 CEALMNKFGFQWPDTLRCEKFPvhgAGELCVGQ---NTSESGTP 127

Cysteine-rich Wnt-binding domain (CRD) of the frizzled 8 (Fz8) receptor; The cysteine-rich domain (CRD) is an essential extracellular portion of the frizzled 8 (Fz8) receptor, and is required for binding Wnt proteins, which play fundamental roles in many aspects of early development, such as cell and tissue polarity, neural synapse formation, and the regulation of proliferation. Fz proteins serve as Wnt receptors for multiple signal transduction pathways, including both beta-catenin dependent and -independent cellular signaling, as well as the planar cell polarity pathway and Ca(2+) modulating signaling pathway. CRD containing Fzs have been found in diverse species from amoebas to mammals. 10 different frizzled proteins are found in vertebrata. Xenopus Fz8 is important in Wnt/beta-catenin signaling pathways controlling the transcriptional activation of target genes Siamois and Xnr3 in the animal caps of late blastula.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 989973164  46 KPPQCVDIPadLRLCHNVGYKKMVLPNLLEHETMAEVKQQASSWVPLLNKNCHIGTQVFLCSLFAPVCLD---RPIYPCR 122
Cdd:cd07461    1 KELQCQEIT--VPLCKGIGYNYTYMPNQFNHDTQDEAGLEVHQFWPLVEIQCSPDLKFFLCSMYTPICLEdykKPLPPCR 78

                         90       100       110
                 ....*....|....*....|....*....|..
gi 989973164 123 WLCEAVRDSCEPVMQFFGFYWPEMLKCDKFPE 154
Cdd:cd07461   79 SVCERAKAGCAPLMRQYGFPWPDRMRCDLLPE 110

Cysteine-rich Wnt-binding domain (CRD) of the frizzled 3 (Fz3) receptor; The cysteine-rich domain (CRD) is an essential extracellular portion of the frizzled 3 (Fz3) receptor, and is required for binding Wnt proteins, which play fundamental roles in many aspects of early development, such as cell and tissue polarity, neural synapse formation, and the regulation of proliferation. Fz proteins serve as Wnt receptors for multiple signal transduction pathways, including both beta-catenin dependent and -independent cellular signaling, as well as the planar cell polarity pathway and Ca(2+) modulating signaling pathway. CRD containing Fzs have been found in diverse species from amoebas to mammals. 10 different frizzled proteins are found in vertebrata. Fz3 plays a vital role in the anterior-posterior guidance of commissural axons. Knockout mice without Fz3 show defects in fiber tracts in the rostral CNS.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 989973164  54 PADLRLCHNVGYKKMVLPNLLEHETMAEVKQQASSWVPLLNKNCHIGTQVFLCSLFAPVCLD--RPIYPCRWLCEAVRDS 131
Cdd:cd07449    7 PITLRMCQDLPYNTTFMPNLLNHYDQQTAALAMEPFHPMVNLECSRDFRPFLCALYAPVCMEygRVTLPCRRLCQRAYSE 86

                         90       100
                 ....*....|....*....|....*
gi 989973164 132 CEPVMQFFGFYWPEMLKCDKFPEGD 156
Cdd:cd07449   87 CSKLMEMFGVPWPEDMECSRFPDCD 111

Cysteine-rich domain of the secreted frizzled-related protein 3 (SFRP3, alias FRZB), a Wnt antagonist; The cysteine-rich domain (CRD) is an essential part of the secreted frizzled-related protein 3 (SFRP3, alias FRZB), which plays important roles in embryogenesis and postnatal development as an antagonist of Wnt proteins, key players in a number of fundamental cellular processes. SFRPs antagonize the activation of Wnt signaling by binding to the CRD domains of frizzled proteins (Fz), thereby preventing Wnt proteins from binding to these receptors. SFRPs are also known to have functions unrelated to Wnt, as enhancers of procollagen cleavage by the TLD proteinases. SFRPs and Fz proteins both contain CRD domains, but SFRPs lack the seven-pass transmembrane domain which is an integral part of Fzs. SFRP3 regulates Wnt signaling activity in bone development and homeostasis. It is also involved in the control of planar cell polarity.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 989973164  54 PADLRLCHNVGYKKMVLPNLLEHETMAEVKQQASSWVPLLNKNCHIGTQVFLCSLFAPVCL----DRPIYPCRWLCEAVR 129
Cdd:cd07441    6 PVRIPMCKSMPWNMTKMPNHLHHSTQANAVLAIEQFEGLLGTQCSPDLLFFLCAMYAPICTidfqHEPIKPCKSVCERAR 85

                         90       100       110
                 ....*....|....*....|....*....|....
gi 989973164 130 DSCEPVMQFFGFYWPEMLKCDKFPEGDVCIAMTP 163
Cdd:cd07441   86 AGCEPVLIRYRHTWPESLACEELPVYDRGVCISP 119

Cysteine-rich domain (CRD) of LIN_17; A cysteine-rich domain (CRD) is an essential component of a number of cell surface receptors, which are involved in multiple signal transduction pathways, particularly in modulating the activity of the Wnt proteins, which play a fundamental role in the early development of metazoans. CRD is also found in secreted frizzled related proteins (SFRPs), which lack the transmembrane segment found in the frizzled protein. The CRD domain is also present in the alpha-1 chain of mouse type XVIII collagen, in carboxypeptidase Z, several receptor tyrosine kinases, and the mosaic transmembrane serine protease corin. The CRD domain is well conserved in metazoans - 10 frizzled proteins have been identified in mammals, 4 in Drosophila and 3 in Caenorhabditis elegans. CRD domains have also been identified in multiple tandem copies in a Dictyostelium discoideum protein. Very little is known about the mechanism by which CRD domains interact with their ligands. The domain contains 10 conserved cysteines. The protein lin-17 is involved in cell type specification during Caenorhabditis elegans vulval development.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 989973164  53 IPADLRLCHNVGYKKMVLPNLLEHETMAEVKQQASSWVPLLNKNCHIGTQVFLCSLFAPVCLDR---PIYPCRWLCEAVR 129
Cdd:cd07454    6 IPIDIELCKDLPYNYTYFPNTILHNDQHTLQTHTEHFKPLMKTKCHPHIHFFICSVFAPMCPIGmpqAVTSCKSVCEQVK 85

                         90       100       110
                 ....*....|....*....|....*....|.
gi 989973164 130 DSCEPVMQFFGFYWPEMLKCDKFP-EGDVCI 159
Cdd:cd07454   86 ADCFSILEEFGIGWPEPLNCAQFPdPPELCM 116

NTR_like domain; a beta barrel with an oligosaccharide/oligonucleotide-binding fold found in netrins, complement proteins, tissue inhibitors of metalloproteases (TIMP), and procollagen C-proteinase enhancers (PCOLCE), amongst others. In netrins, the domain plays a role in controlling axon branching in neural development, while the common function of these modules in TIMPs appears to be binding to metzincins. A subset of this family is also known as the C345C domain because it occurs as a C-terminal domain in complement C3, C4 and C5. In C5, the domain interacts with various partners during the formation of the membrane attack complex.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 989973164 192 EHLCASEFALRMKIKEVKKENGDKKIVPKKKKPLKLGPIkKKELKKLVLYLKNGADCPCHQLDNLSHHFLIMGRKVKSQY 271
Cdd:cd03523    1 KAFCKSDYVVRAKIKEIKEENDDVKYEVKIIKIYKTGKA-KADKADLRFYYTAPACCPCHPILNPGREYLIMGKEEDSQG 79

                         90       100       110
                 ....*....|....*....|....*....|
gi 989973164 272 LL-----TAIHKWDKKNKefknFMKKMKNH 296
Cdd:cd03523   80 GLvldplSFVEPWSPLSL----RQDRRLRE 105

Cysteine-rich domain of carboxypeptidase Z, a member of the carboxypeptidase E family; The cysteine-rich-domain (CRD) is an essential part of carboxypeptidase Z, a member of the carboxypeptidase E family of metallocarboxypeptidases. This is a group of Zn-dependent enzymes implicated in the intra- and extracellular processing of proteins. Carboxypeptidase Z removes C-terminal basic amino acid residues from its substrates, particularly arginine. The CRD acts as a ligand-binding domain for Wnts involved in developmental processes. CPZ binds and may process Wnt-4, CPZ has also been found to enhance the induction of the homeobox gene Cdx1. During vertebrate embryogenesis, the CRD of CPZ upregulates Pax3, a Wnt reporter gene essential for patterning of somites and limb development.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 989973164  48 PQCVDIpaDLRLCHNVGYKKMVLPNLLEHETMAEVKQQA-----SSWVPLLNKNCHIGTQVFLCSLFAPVCL-DRPIYPC 121
Cdd:cd07447    2 ATCTDL--LLSYCSDVSYTQTTFPNLLGHRSREVTEAGAeylllSVLHGLLGGECNPDIRLLGCSVLAPRCEnDKVIKPC 79

                         90       100       110
                 ....*....|....*....|....*....|.
gi 989973164 122 RWLCEAVRDSCEPVMQFFGFYWPEMLKCDKF 152
Cdd:cd07447   80 RSTCEALRKRCSHAFDAIQMAWPYFLDCDRF 110

Netrin C-terminal Domain;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 989973164   191 IEHLCASE--FALRMKIKEVKKENGDKKIVPKKKKPLKLGPIKKKELKKLVLYLKNGADCPCHQLDNLSHHFLIMGRKV- 267
Cdd:smart00643   1 LEKACKSDvdYVYKVKVLSVEEEGGFDKYTVKILEVIKSGTDELVRGKNKLRVFISRASCRCPLLLKLGKSYLIMGKSGd 80

                           90       100       110
                   ....*....|....*....|....*....|....
gi 989973164   268 ------KSQYLLTA---IHKWDKKNK-EFKNFMK 291
Cdd:smart00643  81 lwdakgRGQYVLGKnswVEEWPTEEEcRLRRLQK 114

UNC-6/NTR/C345C module; Sequence similarity between netrin UNC-6 and C345C complement protein family members, and hence the existence of the UNC-6 module, was first reported in. Subsequently, many additional members of the family were identified on the basis of sequence similarity between the C-terminal domains of netrins, complement proteins C3, C4, C5, secreted frizzled-related proteins, and type I pro-collagen C-proteinase enhancer proteins (PCOLCEs), which are homologous with the N-terminal domains of tissue inhibitors of metalloproteinases (TIMPs). The TIMPs are classified as a separate family in Pfam (pfam00965). This expanded domain family has been named as the NTR module.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 989973164  192 EHLCA-SEFALRMKIKEVKKENGDKKIVPKKKKPLKLGpiKKKELKKLVLYLKNGADCPCHQLdNLSHHFLIMGRKV--- 267
Cdd:pfam01759   1 KKACKgSDYVYKVKVLSVEEEGSFDKYTVKVKEVLKEG--TDKIQRGKVRLFLKRGDCRCPQL-RLGKEYLIMGKVGdle 77

                          90       100
                  ....*....|....*....|....*....
gi 989973164  268 --------KSQYLLTAIHKWDKKNKEFKN 288
Cdd:pfam01759  78 grgryvldKNSWVEPWPTKWECKLRELQK 106