ELM
The Eukaryotic Linear Motif resource for
Functional Sites in Proteins
«LIG_FXI_DFP_1« »LIG_G3BP_FGDF_1»

LIG_FZD_DVL_PDZ

Accession:
Functional site class:
The DVL binding motif in Frizzled
Functional site description:
The Dishevelled (Dvl) protein is conserved in both flies and vertebrates and acts as a critical component of Wnt signalling. This intracellular protein binds to Frizzled (FZD) and functions in both canonical and noncanonical Wnt pathways. It relays Wnt signals from the receptors to the downstream effectors. The Wnt/β catenin pathway is initiated by the binding of Wnt to the FZD, which further recruits the co-receptor LRP5/6 in an oligomeric complex. Further, Wnt induced structural/conformational change in the FZD receptor facilitates the recruitment of Dvl to the plasma membrane. The Dvl-FZD interaction occurs between the Dvl PDZ domain and an internal motif (KTXXXW) of FZD.
ELM Description:
The interaction between the PDZ domain of Dvl and the short internal motif present in its targets regulates the Wnt pathway and is important for the membrane localization and phosphorylation of Dvl. The Dvl binds to the internal motif of FZD and not the carboxy terminal site. The K....W is the minimum region required for the PDZ binding although a high affinity interaction site is formed by using the region that spans the KXXXXW motif on its N- and C-terminal sides (Punchihewa,2009). Studies have shown that the lysine and the last hydrophobic residue in the motif are invariant. Moreover, this motif is present in all the members of Frizzled receptors but all of them do not necessarily interact with the Dvl. In case of the Smoothened (SMO) receptors, a variant of this motif exists and the motif sequence is changed to KATXXXW. A X-ray structure of SMO has shown that the motif is part of the helix and Threonine (T-541) participates in the H-bond formation with Valine (V-536) of helix VII (Wang,2013). Additionally, conservation of few other adjacent residues is also seen which are present towards the N-terminus of this motif. These are mainly hydrophobic {W (position620)-[VIL]-[WYG]-[ST]-[AGSK] (position624)} although the presence of small and polar amino acids is observed in two positions (positions are as per human FZD1).

Surprisingly, in the case of FZD3 and FZD6 there is a substitution of [WY] to Glycine (G), which is earmarked by the simultaneous presence of another lysine (K) residue in the position after Serine/Threonine (W-V-G-S-K-K-T-X-X-X-W). The Lysine (FZD6 (Human) – K497, FZD3 (Human) - K501) at this position is only present in this family of frizzled receptors. The simultaneous disappearance of W/Y and appearance of K might lead to the change in specificity of the protein.

Overall, importance of this motif can be reflected by the fact that mutations in the motif lead to the disruption of Wnt signalling.
Pattern: W.{0,1}[VIL].[ST].KA{0,1}T...W
Pattern Probability: 8.743e-09
Present in taxon: Metazoa
Interaction Domain:
PDZ (PF00595) PDZ domain (Also known as DHR or GLGF) (Stochiometry: 1 : 1)
o See 9 Instances for LIG_FZD_DVL_PDZ
o Abstract
The Wnt signalling pathway controls diverse events in the cellular organisms ranging from developmental events to homeostasis. There are many critical components in the Wnt pathway that are required for the efficient signal transduction. Dishevelled (Dvl) is among these components and it transduces the signal from frizzleds (FZD) to downstream components of the Wnt pathway. The Dvl also acts as a branch point by transducing the signal into three different cellular routes (Wallingford,2005). In terms of domain composition it consists of three domains viz. DIX, PDZ and DEP. Importantly, it acts as an intracellular scaffold and interacts with numerous partners. The Dvl PDZ domain is responsible for many of these interactions. This domain is highly flexible and can mediate interaction through the typical PDZ binding motif (Gloy,2002) as well as through an internal motif (Zhang,2009), which is present in the case of FZD. The internal motif of FZD lacks a free C-terminus and binds with the PDZ domain of Dvl directly, which enables the latter to transduce the signal from FZD to downstream components of the Wnt pathway (Wong,2003).

Interestingly, the C-terminal cytoplasmic region of all known FZD receptors differs in length and sequence similarity. As a result, all FZD do not bind to Dvl and hence may have distinct function depending on the Wnt ligand they interact with (Umbhauer,2000). Furthermore, the binding affinity varies depending on the Dvl (1-3) - FZD (1-10) pair. The Dvl internal binding motif generally has a consensus sequence pattern of KT...W, which is located two amino acids after the seventh TM helix. This is the minimum region required for the protein interaction and mutations in any of these conserved residues can disrupt the Wnt/β-catenin signalling which signifies the biological function of the motif (Umbhauer,2000).

The same motif is also utilized by other proteins like Idax, which negatively regulate the Wnt pathway (London,2004). The interaction of the Dlg protein with this motif is known to regulate the spindle orientation in the PCP pathway (Garcia,2014).
o 7 selected references:


o 9 GO-Terms:
Biological Process:
Activation Of Protein Kinase Activity (also annotated in these classes: DOC_GSK3_Axin_1 DOC_RSK_DDVF_1 )
Regulation Of Catenin Import Into Nucleus (also annotated in these classes: DOC_GSK3_Axin_1 )
Positive Regulation Of Protein Ubiquitination Involved In Ubiquitin-Dependent Protein Catabolic Process (also annotated in these classes: DOC_ANK_TNKS_1 DOC_GSK3_Axin_1 )
Canonical Wnt Signaling Pathway Involved In Neural Plate Anterior/Posterior Pattern Formation (also annotated in these classes: DOC_GSK3_Axin_1 )
Cellular Compartment:
Cytosol (also annotated in these classes: CLV_C14_Caspase3-7 CLV_Separin_Fungi CLV_Separin_Metazoa DEG_APCC_DBOX_1 DEG_APCC_KENBOX_2 DEG_APCC_TPR_1 DEG_Cend_DCAF12_1 DEG_Cend_FEM1AC_1 DEG_Cend_FEM1B_2 DEG_Cend_KLHDC2_1 DEG_Cend_TRIM7_1 DEG_COP1_1 DEG_CRBN_cyclicCter_1 DEG_Kelch_actinfilin_1 DEG_Kelch_Keap1_1 DEG_Kelch_Keap1_2 DEG_Kelch_KLHL12_1 DEG_Kelch_KLHL3_1 DEG_MDM2_SWIB_1 DEG_Nend_Nbox_1 DEG_Nend_UBRbox_1 DEG_Nend_UBRbox_2 DEG_Nend_UBRbox_3 DEG_Nend_UBRbox_4 DEG_ODPH_VHL_1 DEG_SCF_FBW7_1 DEG_SCF_FBW7_2 DEG_SCF_FBXO31_1 DEG_SCF_SKP2-CKS1_1 DEG_SCF_TRCP1_1 DEG_SIAH_1 DOC_AGCK_PIF_1 DOC_AGCK_PIF_2 DOC_AGCK_PIF_3 DOC_ANK_TNKS_1 DOC_CDC14_PxL_1 DOC_CKS1_1 DOC_CYCLIN_D_Helix_1 DOC_CYCLIN_RevRxL_6 DOC_CYCLIN_RxL_1 DOC_CYCLIN_yClb1_LxF_4 DOC_CYCLIN_yClb3_PxF_3 DOC_CYCLIN_yCln2_LP_2 DOC_GSK3_Axin_1 DOC_MAPK_DCC_7 DOC_MAPK_FxFP_2 DOC_MAPK_gen_1 DOC_MAPK_GRA24_9 DOC_MAPK_HePTP_8 DOC_MAPK_JIP1_4 DOC_MAPK_MEF2A_6 DOC_MAPK_NFAT4_5 DOC_MAPK_RevD_3 DOC_MIT_MIM_1 DOC_PP1_MyPhoNE_1 DOC_PP1_RVXF_1 DOC_PP1_SILK_1 DOC_PP2A_B56_1 DOC_PP2A_KARD_1 DOC_PP2B_LxvP_1 DOC_PP2B_PxIxIT_1 DOC_PUB_PIM_1 DOC_RSK_DDVF_1 DOC_SPAK_OSR1_1 DOC_TBK1_STING_1 DOC_WD40_RPTOR_TOS_1 DOC_WW_Pin1_4 LIG_14-3-3_CanoR_1 LIG_14-3-3_ChREBP_3 LIG_14-3-3_CterR_2 LIG_ActinCP_CPI_1 LIG_ActinCP_TwfCPI_2 LIG_Actin_RPEL_3 LIG_Actin_WH2_1 LIG_Actin_WH2_2 LIG_ANK_PxLPxL_1 LIG_AP2alpha_1 LIG_AP2alpha_2 LIG_APCC_ABBA_1 LIG_APCC_Cbox_1 LIG_APCC_Cbox_2 LIG_AP_GAE_1 LIG_Arc_Nlobe_1 LIG_ARL_BART_1 LIG_BH_BH3_1 LIG_BIR_II_1 LIG_BIR_III_1 LIG_BIR_III_2 LIG_BIR_III_3 LIG_BIR_III_4 LIG_CaM_1-14-15-16_REV_1 LIG_CaM_1-26_7 LIG_CaM_1-5-10-14_3 LIG_CaM_1-8-14_4 LIG_CaM_1-8-9-10_5 LIG_CaM_1-8_REV_2 LIG_CaM_IQ_9 LIG_CaMK_CASK_1 LIG_CaM_NSCaTE_8 LIG_CAP-Gly_1 LIG_CAP-Gly_2 LIG_Clathr_ClatBox_1 LIG_Clathr_ClatBox_2 LIG_CNOT1_NIM_1 LIG_CSK_EPIYA_1 LIG_CtBP_PxDLS_1 LIG_deltaCOP1_diTrp_1 LIG_DLG_GKlike_1 LIG_Dynein_DLC8_1 LIG_EABR_CEP55_1 LIG_EF_ALG2_ABM_1 LIG_EF_ALG2_ABM_2 LIG_EH_1 LIG_eIF4E_1 LIG_eIF4E_2 LIG_EVH1_1 LIG_EVH1_2 LIG_EVH1_3 LIG_FAT_LD_1 LIG_FERM_MyoX_1 LIG_G3BP_FGDF_1 LIG_GBD_Chelix_1 LIG_GBD_WASP_1 LIG_GSK3_LRP6_1 LIG_GYF LIG_IBAR_NPY_1 LIG_IRF7_LxLS_2 LIG_IRFs_LxIS_1 LIG_KLC1_WD_1 LIG_KLC1_Yacidic_2 LIG_LIR_Apic_2 LIG_LIR_Gen_1 LIG_LIR_LC3C_4 LIG_LIR_Nem_3 LIG_LYPXL_L_2 LIG_LYPXL_S_1 LIG_LYPXL_yS_3 LIG_MYND_3 LIG_OCRL_FandH_1 LIG_PAM2_1 LIG_PAM2_2 LIG_PDZ_Class_1 LIG_PDZ_Class_2 LIG_PDZ_Class_3 LIG_PDZ_Wminus1_1 LIG_Pex14_1 LIG_Pex14_2 LIG_Pex14_3 LIG_Pex14_4 LIG_Pex3_1 LIG_PIP2_ANTH_1 LIG_PIP2_ENTH_1 LIG_PROFILIN_1 LIG_PTAP_UEV_1 LIG_PTB_Apo_2 LIG_PTB_Phospho_1 LIG_SH2_CRK LIG_SH2_GRB2like LIG_SH2_NCK_1 LIG_SH2_PTP2 LIG_SH2_SFK_2 LIG_SH2_SFK_CTail_3 LIG_SH2_STAT3 LIG_SH2_STAT5 LIG_SH2_STAT6 LIG_SH3_1 LIG_SH3_2 LIG_SH3_3 LIG_SH3_4 LIG_SH3_CIN85_PxpxPR_1 LIG_SH3_PxRPPK_7 LIG_SH3_PxxDY_5 LIG_SH3_PxxPPRxxK_8 LIG_SH3_PxxxRxxKP_6 LIG_SPRY_1 LIG_SUFU_1 LIG_SxIP_EBH_1 LIG_TPR LIG_TRAF2like_MATH_loPxQ_2 LIG_TRAF2like_MATH_shPxQ_1 LIG_TRAF3_MATH_PxP_3 LIG_TRAF4_MATH_1 LIG_TRAF6_MATH_1 LIG_TYR_ITAM LIG_TYR_ITIM LIG_TYR_ITSM LIG_UFM1_UFIM_1 LIG_VCP_SHPBox_1 LIG_VCP_VBM_3 LIG_VCP_VIM_2 LIG_Vh1_VBS_1 LIG_WH1 LIG_WRC_WIRS_1 LIG_WW_1 LIG_WW_2 LIG_WW_3 MOD_AAK1BIKe_LxxQxTG_1 MOD_CAAXbox MOD_CDC14_SPxK_1 MOD_CDK_SPK_2 MOD_CDK_SPxK_1 MOD_CDK_SPxxK_3 MOD_CK1_1 MOD_CK2_1 MOD_DYRK1A_RPxSP_1 MOD_GSK3_1 MOD_LATS_1 MOD_LOK_YxT_1 MOD_NEK2_1 MOD_NEK2_2 MOD_NMyristoyl MOD_PIKK_1 MOD_PK_1 MOD_PKA_1 MOD_PKA_2 MOD_PKB_1 MOD_PLK MOD_Plk_1 MOD_Plk_2-3 MOD_Plk_4 MOD_PRMT_GGRGG_1 MOD_ProDKin_1 MOD_SPalmitoyl_2 MOD_SPalmitoyl_4 MOD_TYR_CSK MOD_TYR_DYR ELM:old_LIG_14-3-3_1 ELM:old_LIG_14-3-3_2 ELM:old_LIG_14-3-3_3 TRG_AP2beta_CARGO_1 TRG_Cilium_Arf4_1 TRG_Cilium_RVxP_2 TRG_DiLeu_BaEn_1 TRG_DiLeu_BaEn_2 TRG_DiLeu_BaEn_3 TRG_DiLeu_BaEn_4 TRG_DiLeu_BaLyEn_6 TRG_DiLeu_LyEn_5 TRG_ENDOCYTIC_2 TRG_ER_diArg_1 TRG_ER_diLys_1 TRG_ER_FFAT_1 TRG_ER_FFAT_2 TRG_Golgi_diPhe_1 TRG_LysEnd_APsAcLL_1 TRG_LysEnd_APsAcLL_3 TRG_LysEnd_GGAAcLL_1 TRG_LysEnd_GGAAcLL_2 TRG_NES_CRM1_1 TRG_NESrev_CRM1_2 TRG_PTS1 TRG_PTS2 )
Beta-Catenin Destruction Complex (also annotated in these classes: DOC_ANK_TNKS_1 DOC_GSK3_Axin_1 LIG_GSK3_LRP6_1 )
Molecular Function:
Signal Transducer (also annotated in these classes: DEG_ODPH_VHL_1 DOC_GSK3_Axin_1 LIG_EVH1_2 LIG_IRF7_LxLS_2 LIG_IRFs_LxIS_1 LIG_LRP6_Inhibitor_1 LIG_TRAF2like_MATH_loPxQ_2 LIG_TRAF2like_MATH_shPxQ_1 LIG_TRAF3_MATH_PxP_3 LIG_TRAF4_MATH_1 LIG_TRAF6_MATH_1 )
Protein Kinase Binding (also annotated in these classes: DEG_Kelch_Keap1_1 DEG_Kelch_Keap1_2 DEG_Kelch_KLHL3_1 DOC_CYCLIN_D_Helix_1 DOC_CYCLIN_RevRxL_6 DOC_CYCLIN_RxL_1 DOC_CYCLIN_yClb3_PxF_3 DOC_CYCLIN_yCln2_LP_2 DOC_GSK3_Axin_1 DOC_MAPK_DCC_7 DOC_MAPK_GRA24_9 DOC_MAPK_MEF2A_6 LIG_IRF7_LxLS_2 LIG_IRFs_LxIS_1 MOD_CDK_SPK_2 MOD_CDK_SPxxK_3 MOD_NEK2_1 MOD_NEK2_2 MOD_Plk_1 MOD_Plk_4 )
Protein Complex Scaffold (also annotated in these classes: DOC_GSK3_Axin_1 DOC_MAPK_JIP1_4 DOC_MAPK_NFAT4_5 LIG_CaMK_CASK_1 )


o 9 Instances for LIG_FZD_DVL_PDZ
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
Q9NPG1 FZD3
FZD3_HUMAN 		497 507 PSVFWVGSKKTCFEWASFFH TP 1 Homo sapiens (Human)
1
Q9ULV1 FZD4
FZD4_HUMAN 		494 504 TSGMWIWSAKTLHTWQKCSN TP 1 Homo sapiens (Human)
1
Q14332 FZD2
FZD2_HUMAN 		538 548 TSGFWIWSGKTLHSWRKFYT TP 1 Homo sapiens (Human)
1
E3UKC9 FzdA
E3UKC9_MNELE 		538 549 STGFWVLLSFKTASNWARLL TP 1 Mnemiopsis leidyi (Sea walnut)
1
O60353 FZD6
FZD6_HUMAN 		493 503 SAVFWVGSKKTCTEWAGFFK TP 1 Homo sapiens (Human)
1
G5EDV1 lin-17
G5EDV1_CAEEL 		492 502 SCLMWVLSAKTVHAWKNFIF TP 1 Caenorhabditis elegans
1
Q9UP38 FZD1
FZD1_HUMAN 		620 630 TSGFWIWSGKTLNSWRKFYT TP 3 Homo sapiens (Human)
O75084 FZD7
FZD7_HUMAN 		547 557 TTGFWIWSGKTLQSWRRFYH TP 8 Homo sapiens (Human)
2
O42579 fzd3
FZD3_XENLA 		496 506 PSVFWVGSKKTCFEWASFFH TP 3 Xenopus laevis (African clawed frog)
1
Please cite: ELM-the Eukaryotic Linear Motif resource-2024 update. (PMID:37962385)

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