Capbinding

Capbinding refers to the set of proteins and protein complexes that specifically recognize and bind the 5' cap structure of eukaryotic messenger RNA. The cap is a modified guanine nucleotide, typically 7-methylguanosine (m7G) linked by a triphosphate bridge to the first nucleotide of the RNA. Capbinding is a key step in multiple stages of RNA metabolism, including transcription, RNA processing, export, stability, and translation.

In the nucleus, a dedicated cap-binding complex (CBC) binds the cap shortly after capping. The canonical nuclear CBC consists of CBP80 and CBP20 in many eukaryotes. This complex assists in 5' end capping maturation, participates in pre-mRNA splicing and 3' end processing, and promotes export of mRNA to the cytoplasm. After export, CBC is typically replaced by cytoplasmic cap-binding proteins to support translation.

In the cytoplasm, the principal cap-binding protein is eIF4E, which binds the cap with high affinity and, together with eIF4G and the RNA helicase eIF4A, forms the eIF4F complex. This complex recruits the ribosome to the mRNA and facilitates scanning from the 5' end to locate the start codon, thereby promoting translation initiation. Additional regulatory interactions influence cap binding and initiation efficiency.

Regulation of capbinding is a major control point for gene expression. 4E-binding proteins (4E-BPs) can sequester eIF4E and prevent eIF4F assembly when hypophosphorylated, linking cap-dependent translation to the mTOR signaling pathway. Kinases such as MNK1/2 can phosphorylate eIF4E, modulating its activity. Cap-binding is also affected by RNA secondary structure, cap analogs, and interacting factors, and it can be targeted by viral proteins during infection.

Capbinding is thus central to RNA stability, export, and efficient translation, with dysregulation implicated in various diseases and serving as a focus for therapeutic research.