43S

The 43S pre-initiation complex (43S PIC) is a key assembly in the initiation phase of eukaryotic protein synthesis. It forms in the cytoplasm and serves as the precursor to the 48S initiation complex that begins translating an mRNA. The 43S PIC primes the ribosome for start-site recognition and translation initiation.

Composition and roles of components:

The core of the 43S PIC is the 40S small ribosomal subunit, which carries initiator methionyl-tRNAi (Met-tRNAi) delivered in a ternary complex with GTP and the initiation factor eIF2. The complex also includes eIF3, which acts as a scaffold and facilitator of subunit joining, and initiation factors eIF1 and eIF1A that help maintain fidelity during scanning. Another essential factor is eIF5, a GTPase-activating protein that promotes GTP hydrolysis on eIF2 at the start codon. Additional associated factors may contribute to assembly and regulation, but the core set listed above defines the canonical 43S PIC.

Function and mechanism:

The 43S PIC is recruited to capped mRNA via interactions between eIF3 and the messenger RNA cap-binding complex eIF4F. Once bound, the complex scans the 5' untranslated region to locate the start codon. Upon start codon recognition, GTP hydrolysis on eIF2 is triggered, leading to the release of some initiation factors and allowing the 60S ribosomal subunit to join, forming the 80S initiation complex and commencing polypeptide synthesis. The transition from 43S to the 48S complex marks the initiation of translation.

Regulation and context:

43S PIC formation is tightly regulated by cellular signaling pathways. For example, phosphorylation of eIF2α during stress reduces the availability of the ternary complex, inhibiting 43S assembly. mTOR signaling influences cap-dependent initiation by modulating eIF4F and related factors, thereby indirectly affecting 43S recruitment. Dysregulation of initiation factors involving the 43S PIC has been implicated in various diseases.