Nicalin is a Nodal signalling antagonist and a distant homologue of the gamma-secretase component Nicastrin []. In humans, Nicalin forms a complex with NOMO (Nodal modulator) and controls the assembly and stability of this complex [].
This is the β-sandwich domain found in ER membrane protein complex subunit 7 (EMC7) [, ], which is an integral membrane component of the EMC. EMC is widely conserved and involved in membrane protein biogenesis. It mediates the insertion into endoplasmic reticulum membranes of newly synthesized membrane proteins in an energy-independent manner, both post-translational insertion of tail-anchored proteins and co-translational insertion of multipass membrane proteins [, ]. This entry includes UPF0620 protein C83.10 from S. pombe, an orthologue from animal EMC7.This domain is also found in nodal modulators, which have been identified as part of a protein complex that participates in the nodal signalling pathway during vertebrate development [].
This entry represents the cerberus family of proteins. Cerberus is a cytokine that may play a role in anterior neural induction and somite formation during embryogenesis, in part through a BMP-inhibitory mechanism []. It can regulate Nodal signalling during gastrulation as well as the formation and patterning of the primitive streak.
This entry contains a prealbumin-like fold domain from a wide variety of bacterial surface proteins. This entry corresponds to domain 1 and domain 3 of SpaA from Corynebacterium diphtheriae []. It is also present in Collagen adhesin []and Trypsin-resistant surface T6 protein from Streptococci species. Some members of this family contain an isopeptide bond.This domain is also found in eukaryotic cell surface proteins including Nodal modulators.
Contactins are cell adhesion molecules that belong to the immunoglobulin superfamily and are involved in neural development []. They usually consist of six N-terminal Ig domains, four fibronectin type III domains, and a C-terminal glycophosphatidylinositol (GPI)-anchor to the extracellular part of the cell membrane [].Contactin-1 (CNTN1) is expressed by a diversity of neurons and contributes to the formation and function of neuronal connections []. Contactin-1 regulates both myelin formation and organisation of nodal and paranodal domains in the central []and peripheral nervous system []. It plays a relevant role in cerebellar ontogenesis []and cerebral cortex development []. Contactin-1 contributes to the invasion and metastasis of several tumours [, ].
Indian hedgehog protein (IHH, MEROPS identifier C46.003) is important for the development and growth of bone and cartilage in the embryo []. IHH is synthesized as a precursor and activates itself by cleavage of Gly-Cys bond, in which the thiol group of the cysteine is the nucleophile []. This results in the release of the N-terminal effector domain, and no further proteolytic activity takes place. The differentiation of chondrocytes in embryonic mouse limbs, induction of the expression of nodal in the lateral plate mesoderm of early chick embryos, and affinities for hedgehog-binding proteins have been compared for Sonic, Indian and Desert hedgehog proteins [].
Proteins in this family include PGAP6 (also known as TMEM8A), NGX6 (also known as TMEM8B) and myomaker (also known as TMEM8C). TMEM8C is embedded in the plasma membrane with seven membrane-spanning regions and a required intracellular C-terminal tail. It is essential for myoblast fusion and sufficient to promote fusion of fibroblasts with muscle cells []. TMEM8A and TMEM8B has no fusogenic activity. TMEM8A is a GPI-specific phospholipase A2 involved in Nodal signaling modulation through CRIPTO shedding []. TMEM8B plays a role in cell adhesion modulation in nasopharyngeal carcinoma cells [].
This is a hydrophilic cysteine-rich ligand-binding domain found in both TGF-beta receptor types (type I and II). In both types, this domain posses a 9 amino acid cysteine box, with the the consensus CCX{4-5}CN. The type I receptors also possess 7 extracellular residues preceding the cysteine box [, , ].The Transforming growth factor-beta superfamily of ligands include: bone morphogenetic proteins (BMPs), growth and differentiation factors (GDFs), anti-mullerian hormone (AMH), activin, nodal and TGF-beta. Signalling begins with the binding of a TGF-beta superfamily ligand to a TGF-beta type II receptors. The type II receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators [].The receptors for most of the members of this growth factor family are related. They are receptor-type kinases of Ser/Thr type, which have a singletransmembrane domain and a specific hydrophilic Cys-rich ligand-binding domain [, , ].
Bicaudal-C (BICC, BICC1 in vertebrates) is an RNA-binding protein with translational repression function []. It is involved in the regulation of embryonic differentiation and plays a role in the regulation of Dvl (Dishevelled) signaling, particularly in the correct cilia orientation and nodal flow generation []. In Drosophila, disruption of BICC can disturb the normal migration direction of the anterior follicle cell of oocytes []. In mammals, mutations in this gene are associated with polycystic kidney disease and it was suggested that the BICC1 protein can indirectly interact with ANKS6 protein (ANKS6 is also associated with polycystic kidney disease) through some protein and RNA intermediates [].BICC1 contains N-terminal K homology RNA-binding vigilin-like repeats and a C-terminal SAM domain. This entry represents the SAM (sterile alpha motif) domain, which is a protein-protein interaction domain [].
