This entry includes Asc1 from yeasts and RACK1 from animals. They are core 40S ribosomal proteins that repress gene expression []. The seven-bladed β-propeller structure of RACK1 is located near the mRNA exit tunnel where it makes contacts with the ribosomal RNA through lysine and arginine residues and neighbouring ribosomal proteins []. RACK1 also serves as a scaffold protein for a wide range of kinases and membrane bound receptors [, ]. It has been shown to regulates axonal growth []and is essential for development in mice, Drosophila melanogaster and Arabidopsis thaliana [, , ].
This family includes eukaryotic translation initiation factor 6 (eIF6) as well as presumed archaeal homologues.The assembly of 80S ribosomes requires joining of the 40S and 60S subunits, which is triggered by the formation of an initiation complex on the 40S subunit. This event is rate-limiting for translation, and depends on external stimuli and the status of the cell. Eukaryotic translation initiation factor 6 (eIF6) binds specifically to the free 60S ribosomal subunit and prevents its association with the 40S ribosomal subunit ribosomes []. Furthermore, eIF6 interacts in the cytoplasm with RACK1, a receptor for activated protein kinase C (PKC). RACK1 is a major component of translating ribosomes, which harbour significant amounts of PKC. Loading 60S subunits with eIF6 caused a dose-dependent translational block and impairment of 80S formation, which are reversed by expression of RACK1 and stimulation of PKC in vivo and in vitro. PKC stimulation leads to eIF6 phosphorylation and its release, promoting 80S subunit formation. RACK1 provides a physical and functional link between PKC signalling and ribosome activation [, , ].All members of this family have a conserved pentameric fold referred to as a beta/alpha propeller. The eukaryotic IF6 members have a moderately conserved C-terminal extension which is not required for ribosomal binding, and may have an alternative function [].
The inositol 1,4,5-trisphosphate receptor (IP(3)R) is a large, endoplasmic reticulum (ER)-resident protein that is a key regulator of intracellular Ca(2+) signalling []. Inositol 1,4,5-trisphosphate is formed in response to the activation of G protein-coupled receptors or tyrosine kinase receptors located in the plasma membrane, which elicit IP(3)R-mediated Ca(2+) release from ER stores [].The IP(3)R contains an N-terminal IP(3) recognition site and a C-terminal Ca(2+)-channel domain; between them is a large interaction domain for regulatory proteins, including calmodulin, chromgranins, glyceraldehyde-3- phosphate dehydrogenase, RACK1 and caldendrin []. These proteins regulate IP(3)R in diverse ways, but only two regulators have been shown to influence Ca(2+) sensitivity [].A protein termed DANGER has been identified as a novel IP(3)R-interacting protein []. DANGER is membrane-associated and predicted to contain a partial MAB-21 domain. It is expressed in a wide variety of neuronal cell lineages, where it localises with IP(3)R to membranes in the cell periphery. DANGER interacts with IP(3)R in vitro and co-immuno- precipitates with IP(3)R from cellular preparations; it robustly enhances Ca(2+)-mediated inhibition of IP(3)R Ca(2+) release without affecting IP(3) binding in microsomal assays, and inhibits gating in single-channel recordings of IP(3)R. The protein appears to allosterically modulate the sensitivity of IP(3)R to Ca(2+) inhibition, which probably alters IP(3)R-mediated Ca(2+) dynamics in cells where DANGER and IP(3)R are co-expressed [].
