This entry includes Nmd2 from yeasts and UPF2 from animals. They are involved in the nonsense-mediated mRNA decay (NMD) pathway [, ]. In the human UPF complex (composed of UPF1/2/3), UPF2 and UPF3b cooperatively stimulate both ATPase and RNA helicase activities of UPF1 [].
UPF1 (or regulator of nonsense transcripts 1 homologue) is an essential RNA helicase that detects mRNAs containing premature stop codons and triggers their degradation. Together with UPF2 and UPF3, forms a surveillance complex, in which UPF2 acts as a bridge between UPF1 and UPF3. UPF2 and UPF3 are nonenzymatic components of the complex that stimulate the activity of UPF1 []. UPF1 has a N-terminal cysteine/histidine-rich zinc-binding domain (CH/ZBD), a regulatory 1B domain, followed by a helicase core that belongs to superfamily 1 (SF1).This is 1B domain of UPF1 which has a regulatory role. It suffers conformational changes from an inhibitory state to a transition-state complex that modulate RNA binding [, ].
UPF1 (or regulator of nonsense transcripts 1 homologue) is an essential RNA helicase that detects mRNAs containing premature stop codons and triggers their degradation. Together with UPF2 and UPF3, forms a surveillance complex, in which UPF2 acts as a bridge between UPF1 and UPF3. UPF2 and UPF3 are nonenzymatic components of the complex that stimulate the activity of UPF1 []. UPF1 has a N-terminal cysteine/histidine-rich zinc-binding domain (CH/ZBD), a regulatory 1B domain, followed by a helicase core that belongs to superfamily 1 (SF1).This is the N-terminal CH/ZBD which contains 3 zinc binding motifs that interacts with UPF2 and it also has a cis-inhibitory effect on the ATPase activity. After binding to UPF2, the CH/ZBD suffers a large conformational change that causes the catalytic helicase domain to bind RNA less extensively and triggering its helicase activity [, ].
Nonsense-mediated mRNA decay (NMD) is a surveillance mechanism by which eukaryotic cells detect and degrade transcripts containing premature termination codons. Three 'up-frameshift' proteins, UPF1, UPF2 and UPF3, are essential for this process in organisms ranging from yeast, human to plants []. Exon junction complexes (EJCs) are deposited ~24 nucleotides upstream of exon-exon junctions after splicing. Translation causes displacement of the EJCs, however, premature translation termination upstream of one or more EJCs triggers the recruitment of UPF1, UPF2 and UPF3 and activates the NMD pathway [, ]. This entry contains UPF3. The crystal structure of the complex between human UPF2 and UPF3b, which are, respectively, a MIF4G (middle portion of eIF4G) domain and an RNP domain (ribonucleoprotein-type RNA-binding domain) has been determined to 1.95A. The protein-protein interface is mediated by highly conserved charged residues in UPF2 and UPF3b and involves the β-sheet surface of the UPF3b ribonucleoprotein (RNP) domain, which is generally used by these domains to bind nucleic acids. In UPF3b the RNP domain does not bind RNA, whereas the UPF2 construct and the complex do. It is clear that some RNP domains have evolved for specific protein-protein interactions rather than as nucleic acid binding modules [].
This entry represents an MIF4G-like domain. MIF4G domains share a common structure but can differ in sequence. This entry is designated "type 2", and is found in nuclear cap-binding proteins and eIF4G.The MIF4G domain is a structural motif with an ARM (Armadillo) repeat-type fold, consisting of a 2-layer alpha/alpha right-handed superhelix. Proteins usually contain two or more structurally similar MIF4G domains connected by unstructured linkers. MIF4G domains are found in several proteins involved in RNA metabolism, including eIF4G (eukaryotic initiation factor 4-gamma), eIF-2b (translation initiation factor), UPF2 (regulator of nonsense transcripts 2), and nuclear cap-binding proteins (CBP80, CBC1, NCBP1), although the sequence identity between them may be low []. The nuclear cap-binding complex (CBC) is a heterodimer. Human CBC consists of a large CBP80 subunit and a small CBP20 subunit, the latter being critical for cap binding. CBP80 contains three MIF4G domains connected with long linkers, while CBP20 has an RNP (ribonucleoprotein)-type domain that associates with domains 2 and 3 of CBP80 []. The complex binds to 5'-cap of eukaryotic RNA polymerase II transcripts, such as mRNA and U snRNA. The binding is important for several mRNA nuclear maturation steps and for nonsense-mediated decay. It is also essential for nuclear export of U snRNAs in metazoans []. Eukaryotic translation initiation factor 4 gamma (eIF4G) plays a critical role in protein expression, and is at the centre of a complex regulatory network. Together with the cap-binding protein eIF4E, it recruits the small ribosomal subunit to the 5'-end of mRNA and promotes the assembly of a functional translation initiation complex, which scans along the mRNA to the translation start codon. The activity of eIF4G in translation initiation could be regulated through intra- and inter-protein interactions involving the ARM repeats []. In eIF4G, the MIF4G domain binds eIF4A, eIF3, RNA and DNA.
This entry represents an MIF4G-like domain. MIF4G domains share a common structure but can differ in sequence. This entry is designated "type 1", and is found in nuclear cap-binding proteins and eIF4G.The MIF4G domain is a structural motif with an ARM (Armadillo) repeat-type fold, consisting of a 2-layer alpha/alpha right-handed superhelix. Proteins usually contain two or more structurally similar MIF4G domains connected by unstructured linkers. MIF4G domains are found in several proteins involved in RNA metabolism, including eIF4G (eukaryotic initiation factor 4-gamma), eIF-2b (translation initiation factor), UPF2 (regulator of nonsense transcripts 2), and nuclear cap-binding proteins (CBP80, CBC1, NCBP1), although the sequence identity between them may be low []. The nuclear cap-binding complex (CBC) is a heterodimer. Human CBC consists of a large CBP80 subunit and a small CBP20 subunit, the latter being critical for cap binding. CBP80 contains three MIF4G domains connected with long linkers, while CBP20 has an RNP (ribonucleoprotein)-type domain that associates with domains 2 and 3 of CBP80 []. The complex binds to 5'-cap of eukaryotic RNA polymerase II transcripts, such as mRNA and U snRNA. The binding is important for several mRNA nuclear maturation steps and for nonsense-mediated decay. It is also essential for nuclear export of U snRNAs in metazoans []. Eukaryotic translation initiation factor 4 gamma (eIF4G) plays a critical role in protein expression, and is at the centre of a complex regulatory network. Together with the cap-binding protein eIF4E, it recruits the small ribosomal subunit to the 5'-end of mRNA and promotes the assembly of a functional translation initiation complex, which scans along the mRNA to the translation start codon. The activity of eIF4G in translation initiation could be regulated through intra- and inter-protein interactions involving the ARM repeats []. In eIF4G, the MIF4G domain binds eIF4A, eIF3, RNA and DNA.
