The Eukaryotic Linear Motif resource for
Functional Sites in Proteins
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:

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
497 507 PSVFWVGSKKTCFEWASFFH TP 1 Homo sapiens (Human)
494 504 TSGMWIWSAKTLHTWQKCSN TP 1 Homo sapiens (Human)
Q14332 FZD2
538 548 TSGFWIWSGKTLHSWRKFYT TP 1 Homo sapiens (Human)
538 549 STGFWVLLSFKTASNWARLL TP 1 Mnemiopsis leidyi (Sea walnut)
O60353 FZD6
493 503 SAVFWVGSKKTCTEWAGFFK TP 1 Homo sapiens (Human)
G5EDV1 lin-17
492 502 SCLMWVLSAKTVHAWKNFIF TP 1 Caenorhabditis elegans
620 630 TSGFWIWSGKTLNSWRKFYT TP 3 Homo sapiens (Human)
O75084 FZD7
547 557 TTGFWIWSGKTLQSWRRFYH TP 8 Homo sapiens (Human)
O42579 fzd3
496 506 PSVFWVGSKKTCFEWASFFH TP 3 Xenopus laevis (African clawed frog)
Please cite: The Eukaryotic Linear Motif resource: 2022 release. (PMID:34718738)

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