InterPro domain: IPR016021

This superfamily represents an MIF4G-like domain. MIF4G domains share a common structure but can differ in sequence. The MIF4G domain is a structural motif with an ARM (Armadillo) repeat-type fold, consisting of a 2-layer alpha/alpha right-handed superhelix. Family members contain two or more structurally similar domains of this fold connected by unstructured linkers; this entry covers types 1, 2 and 3 MIF4G-like domains. 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 [ 1 ].

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 [ 2 ]. 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 [ 3 ].

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 [ 4 ]. In eIF4G, the MIF4G domain binds eIF4A, eIF3, RNA and DNA.

Nonsense-mediated mRNA decay (NMD) in eukaryotes involves UPF1, UPF2 and UPF3 to accelerate the decay rate of two unique classes of transcripts: (1) nonsense mRNAs that arise through errors in gene expression, and (2) naturally occurring transcripts that lack coding errors but have built-in features that target them for accelerated decay (error-free mRNAs). NMD can trigger decay during any round of translation and can target CBC-bound or eIF-4E-bound transcripts [ 5 ]. UPF2 contains MIF4G domains, while UPF3 contains an RNP domain [ 6 ].

1. Eukaryote-specific domains in translation initiation factors: implications for translation regulation and evolution of the translation system. Genome Res. 10, 1172-84
2. Crystal structure of the human nuclear cap binding complex. Mol. Cell 8, 383-96
3. Specificity of recognition of mRNA 5' cap by human nuclear cap-binding complex. RNA 11, 1355-63
4. eIF4G and CBP80 share a common origin and similar domain organization: implications for the structure and function of eIF4G. Biochemistry 44, 12265-72
5. Transcript selection and the recruitment of mRNA decay factors for NMD in Saccharomyces cerevisiae. RNA 11, 1333-9
6. The structural basis for the interaction between nonsense-mediated mRNA decay factors UPF2 and UPF3. Nat. Struct. Mol. Biol. 11, 330-7