This entry represents a domain found in the cell-fate determinant Numb, and in related proteins. In Drosophila, two signalling pathways, one mediated by Numb and the other by Notch, play essential but antagonistic roles in enabling the two daughters to adopt different fates after a wide variety of asymmetric cell divisions []. Numb acts to inhibit Notch signalling, this inhibition being critical for many cell fate decisions []. Mammalian Numb (mNumb) has multiple functions and plays important roles in the regulation of neural development, including maintenance of neural progenitor cells and promotion of neuronal differentiation in the central nervous system (CNS) [].
This group represents Protein numb and similar proteins from animals. This protein plays key roles in cell fate determination []. Members of this protein family contain a PID domain, a type of PTB domain []. NUMB from Drosophila is required in determination of cell fate during sensory organ formation in embryos []. It recruits alpha-Adaptin, and this physical interaction plays a role in downregulating Notch, presumably by stimulating endocytosis of Notch [, ]. Numb-related protein 1 (NUMB1) from Caenorhabditis elegans is involved in the tethering and targeting of pkc-3 to modulate the intracellular distribution of the kinase []. Mammalian Numb-like protein (NUMBL) plays a role in the process of neurogenesis and is required throughout embryonic neurogenesis to maintain neural progenitor cells []. It inhibits glioma cell migration and invasion by suppressing TRAF5-mediated NF-kappaB activation []. It has a role in tumorigenesis [].
Pleckstrin homology (PH) domains are small modular domains that occur in a large variety of signalling proteins, where they serve as simple targeting domains that bind lipids [, , ]. PH domains have a partly opened β-barrel topology that is capped by an alpha helix. The structure of PH domains is similar to the phosphotyrosine-binding domain (PTB) found in IRS-1 (insulin receptor substrate 1) [], Shc adaptor and Numb []; to the Ran-binding domain, found in Nup nuclear pore complex and Ranbp1 []; to the Enabled/VASP homology domain 1 (EVH1 domain), found in Enabled, VASP (vasodilator-stimulated phosphoprotein), Homer and WASP actin regulatory protein []; and to the third domain of FERM, found in moesin, radixin, ezrin, merlin and talin [].This superfamily represents the PH domain and structurally related domains.
This entry represents the RNA recognition motif 2 (RRM2) of Musashi-1, which is a highly conserved RNA binding protein that was initially identified in Drosophila by its ability to regulate sensory organ development and asymmetric cell division []. Mammalian Musashi-1 has multiple functions in normal and abnormal processes by mediating different post-transcriptional processes. It has been implicated in the maintenance of the stem-cell state, differentiation, and tumorigenesis. It translationally regulates the expression of a mammalian numb gene by binding to the 3'-untranslated region of mRNA of Numb, encoding a membrane-associated inhibitor of Notch signaling, and further influences neural development []. Moreover, Musashi-1 represses translation by interacting with the poly(A)-binding protein and competes for binding of the eukaryotic initiation factor-4G (eIF-4G) [].Proteins containing this domain also includes Musashi-2, which has been identified as a regulator of the hematopoietic stem cell (HSC) compartment and of leukemic stem cells after transplantation of cells with loss and gain of function of the gene []. It influences proliferation and differentiation of HSCs and myeloid progenitors, and further modulates normal hematopoiesis and promotes aggressive myeloid leukemia [, ]. Musashi-1 and Musashi-2 contain two conserved N-terminal tandem RNA recognition motifs (RRMs), also termed RBDs (RNA binding domains) or RNPs (ribonucleoprotein domains), along with other domains of unknown function
This entry represents the RNA recognition motif 1 (RRM1) of Musashi-1, which is a highly conserved RNA binding protein that was initially identified in Drosophila by its ability toregulate sensory organ development and asymmetric cell division []. Mammalian Musashi-1 has multiple functions in normal and abnormal processes by mediating different post-transcriptional processes. It has been implicated in the maintenance of the stem-cell state, differentiation, and tumorigenesis. It translationally regulates the expression of a mammalian numb gene by binding to the 3'-untranslated region of mRNA of Numb, encoding a membrane-associated inhibitor of Notch signaling, and further influences neural development []. Moreover, Musashi-1 represses translation by interacting with the poly(A)-binding protein and competes for binding of the eukaryotic initiation factor-4G (eIF-4G) [].Proteins containing this domain also includes Musashi-2, which has been identified as a regulator of the hematopoietic stem cell (HSC) compartment and of leukemic stem cells after transplantation of cells with loss and gain of function of the gene []. It influences proliferation and differentiation of HSCs and myeloid progenitors, and further modulates normal hematopoiesis and promotes aggressive myeloid leukemia [, ]. Musashi-1 and Musashi-2 contain two conserved N-terminal tandem RNA recognition motifs (RRMs), also termed RBDs (RNA binding domains) or RNPs (ribonucleoprotein domains), along with other domains of unknown function.
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. SINA/Siah family proteins represent mammalian homologs of the Drosophila SINA (seven in absentia) protein. SINA is required for R7 photoreceptor cell differentiation within the sevenless pathway []. Members of this family are E3 ubiquitin ligases that regulate ubiquitination and protein degradation. Siahs are known to recognise several target proteins including Deleted in Colorectal Cancer (DCC), synaptophysin and Numb and promote their degradation [, ]. SINA/Siah sequences are highly conserved from plants to mammals. Whereas the N terminus and RING domain of Siah bind E2 proteins, the C terminus can be considered as a substrate- and cofactor-interaction domain (substrate-binding domain, SBD) that interacts with a number of proteins, some of which are degraded []. The SBD domain displays some sequence similarities with the C-terminal region of TRAF proteins. It contains a cysteine-rich region, the SIAH-type zinc finger, with eight totally conserved Cys and His residues that coordinate two zinc atoms []. The crystal structure of SIAH-type zinc finger has been solved []. It folds in two subdomains, each one binding one zinc atom and consisting of two β-strands and an alpha helice.
