This domain family is found in eukaryotes, and is typically between 54 and 99 amino acids in length. The family is found in association with . CK1gamma is a membrane-bound member of the CK1 family. Gain-of-function and loss-of-function experiments show that CK1gamma is both necessary and sufficient to transduce LRP6 signalling in vertebrates and Drosophila cells.
Ly6/PLAUR domain-containing protein 6 (LYPD6) is a higher eukaryotic protein expressed in neurons. It modulates nicotinic acetylcholine receptors by selectively increasing Ca2+-influx through this ion channel []. LYPD6 carries an LU protein domain - about 80 amino acids long characterised by a conserved pattern of 10 cysteine residues []. It is a positive feedback regulator of Wnt/beta-catenin signalling, e.g. for patterning of the mesoderm and neuroectoderm in zebrafish gastrulation, where Lypd6 is GPI-anchored to the plasma-membrane and interacts with the Wnt receptor Frizzled8 and the co-receptor Lrp6 [].
Transmembrane protein 131-like (TMEM131L) was identified as a negative regulator of thymocyte proliferation that acts through mixed Wnt-dependent and independent mechanisms. It has two isoforms, L and S, which have different subcellular localisation. L isoform, the membrane-associated form, inhibits canonical Wnt/beta-catenin signalling through the induction of lysosome-dependent degradation of the active phosphorylated form of the LRP6 coreceptor. This protein contains three conserved homology domains (CHD1, 2 and 3), a transmembrane region and a C-terminal serine-rich region []. This entry represents a conserved domain found in TMEM131 and TMEM131L. This domain is C-terminal to the CHD1 domain.
This entry includes Ly6/PLAUR domain-containing protein 6 and Ly6/PLAUR domain-containing protein 6B (LYPD6/6B). They are prototoxins that belong to a larger family known as Ly-6/urokinase plasminogen activator receptor (Ly6/uPAR). They have 8-10 conserved cysteine residues that allow for the formation of disulfide bonds, constraining the protein to the 3-fingered motif secondary structure [].Ly6/PLAUR domain-containing protein 6 (LYPD6) is a higher eukaryotic protein expressed in neurons. It modulates nicotinic acetylcholine receptors by selectively increasing Ca2+-influx through this ion channel []. LYPD6 carries an LU protein domain - about 80 amino acids long characterised by a conserved pattern of 10 cysteine residues []. It is a positive feedback regulator of Wnt/beta-catenin signalling, e.g. for patterning of the mesoderm and neuroectoderm in zebrafish gastrulation, where Lypd6 is GPI-anchored to the plasma-membrane and interacts with the Wnt receptor Frizzled8 and the co-receptor Lrp6 [].LYPD6B has been shown to modulate heteromeric alpha3beta4-containing nicotinic acetylcholine receptors [].
LRP5/6 are transmembrane receptors that are involved in Wnt signal transduction []. Binding of the Wnts to LRP5/6 and their participating co-receptors, the frizzled (Fz) family of 7 transmembrane spanning proteins, results in a series of downstream intracelullar events, in particular the inhibition by subsequent phosphorylation of GSK-3beta []. LRP5/6 have been shown to play an role in bone homeostasis []. Mutations in the LRP5 gene cause vitreoretinopathy, exudative 4 (EVR4), a disorder of the retinal vasculature characterised by an abrupt cessation of growth of peripheral capillaries, leading to an avascular peripheral retina []. Mutations in the LRP6 gene cause coronary artery disease, autosomal dominant, 2 (ADCAD2), a common heart disease characterised by reduced or absent blood flow in one or more of the arteries that encircle and supply the heart [].
RSPO1 is a secreted protein that belongs to the R-spondin (RSPO) family. It regulates Wnt signalling by inhibiting internalization of LRP6 []. It also regulates the canonical Wnt/beta-catenin-dependent pathway and non-canonical Wnt signalling by acting as an inhibitor of ZNRF3, an important regulator of the Wnt signalling pathway []. The R-spondin (RSPO) family is a small group of four secreted proteins (RSPO1-RSPO4) that have pleiotropic functions in development and stem cell growth by strongly enhancing Wnt pathway activation. They contain an N-terminal secretory signal peptide sequence, two tandem furin-like cysteine-rich (Fu-CRD) domains, a thrombospondin type I repeat (TSP) domain, and a C-terminal basic amino acid-rich (BR) domain. Leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4), LGR5, and LGR6 have been identified as receptors for RSPOs [].
LRP chaperone MESD (also known as mesoderm development candidate 2) represents a set of highly conserved proteins found from nematodes to humans. It is a chaperone that specifically assists with the folding of β-propeller/EGF modules within the family of low-density lipoprotein receptors (LDLRs). It also acts as a modulator of the Wnt pathway, since some LDLRs are coreceptors for the canonical Wnt pathway and is essential for specification of embryonic polarity and mesoderm induction []. The Drosophila homologue, known as boca, is an endoplasmic reticulum protein required for wingless signaling and trafficking of LDL receptor family members [].The final C-terminal residues, KEDL, are the endoplasmic reticulum retention sequence as it is an ER protein specifically required for the intracellular trafficking of members of the low-density lipoprotein family of receptors (LDLRs) []. The N- and C-terminal sequences are predicted to adopt a random coil conformation, with the exception of an isolated predicted helix within the N-terminal region, The central folded domain flanked by natively unstructured regions is the necessary structure for facilitating maturation of LRP6 (Low-Density Lipoprotein Receptor-Related Protein 6 Maturation) [].
This entry represents the RING-type zinc finger domain of E3 ubiquitin-protein ligase RNF43. Proteins containing this domain are found in vertebrates. RNF43 acts as a negative regulator of the Wnt signaling pathway by mediating the ubiquitination and subsequent degradation of Wnt receptor complex components Frizzled and LRP6 [, , ]. RNF43 also interacts with NEDD-4-like ubiquitin-protein ligase-1 (NEDL1) and regulates p53-mediated transcription []. It may also be involved in cell growth control potentially through the interaction with, a chromatin-associated protein interfacing the nuclear envelope []. Mutations of RNF43 have been identified in various tumours, including colorectal cancer (CRC), endometrial cancer, mucinous ovarian tumours, gastric adenocarcinoma, pancreatic ductal adenocarcinoma, liver fluke-associated cholangiocarcinoma, hepatocellular carcinoma, and glioma [, , ]. RNF43 contains an N-terminal signal peptide, a protease-associated (PA) domain, a transmembrane (TM) domain and a C3H2C3-type RING-H2 finger domain followed by a long C-terminal region [].In frogs (Xenopus), ZNRF3 and RNF43 were seen to play a key role in limb specification, constituting a master switch along with RSPO2, which may have implications for regenerative medicine [].
This entry represents the RING-type zinc finger domain of E3 ubiquitin-protein ligase ZNRF3 (Zinc/RING finger protein 3), a transmembrane enzyme () homologue of Ring finger protein 43 (RNF43). It is predominantly found in vertebrates.In humans, ZNRF3 acts as a negative regulator of the Wnt signaling pathway by mediating the ubiquitination and subsequent degradation of Wnt receptor complex components Frizzled and LRP6 [, , ]. ZNRF3 also functions as a tumour suppressor in the intestinal stem cell zone by restricting the size of the intestinal stem cell zone []. In frogs (Xenopus), ZNRF3 and RNF43 were seen to play a key role in limb specification, constituting a master switch along with RSPO2, which may have implications for regenerative medicine []. Zinc finger (Znf) domains are relatively small protein motifs which contain multiple finger-like protrusions that make tandem contacts with their target molecule. Some of these domains bind zinc, but many do not; instead binding other metals such as iron, or no metal at all. For example, some family members form salt bridges to stabilise the finger-like folds. They were first identified as a DNA-binding motif in transcription factor TFIIIA from Xenopus laevis (African clawed frog), however they are now recognised to bind DNA, RNA, protein and/or lipid substrates [, , , , ]. Their binding properties depend on the amino acid sequence of the finger domains and of the linker between fingers, as well as on the higher-order structures and the number of fingers. Znf domains are often found in clusters, where fingers can have different binding specificities. There are many superfamilies of Znf motifs, varying in both sequence and structure. They display considerable versatility in binding modes, even between members of the same class (e.g. some bind DNA, others protein), suggesting that Znf motifs are stable scaffolds that have evolved specialised functions. For example, Znf-containing proteins function in gene transcription, translation, mRNA trafficking, cytoskeleton organisation, epithelial development, cell adhesion, protein folding, chromatin remodelling and zinc sensing, to name but a few []. Zinc-binding motifs are stable structures, and they rarely undergo conformational changes upon binding their target.
