EIF2AK1

EIF2AK1, also known as HRI (Heme-Regulated Inhibitor) or PK R-like kinase (double-stranded RNA-activated protein kinase PKR), is a gene that encodes a protein kinase. This protein is a member of the eukaryotic initiation factor 2 alpha kinase family, which are crucial regulators of protein synthesis. Specifically, EIF2AK1 plays a role in the cellular response to various stress conditions, including oxidative stress and the presence of heme.

The protein kinase activity of EIF2AK1 is regulated by heme. In normal cellular conditions, heme binds to EIF2AK1 and inhibits its kinase activity. However, under conditions of heme deficiency or other cellular stresses, the inhibition is relieved, and EIF2AK1 becomes active. Once activated, EIF2AK1 phosphorylates the alpha subunit of eukaryotic initiation factor 2 (eIF2α). This phosphorylation event leads to the formation of a stable ternary complex between eIF2α, GTP, and initiator tRNA.

The phosphorylated eIF2α then acts as a dominant-negative inhibitor of the eIF2B guanine nucleotide exchange factor, effectively shutting down global protein synthesis. This global shutdown is a protective mechanism that allows the cell to conserve energy and resources during stress. However, the translation of specific mRNAs, particularly those containing upstream open reading frames, may be selectively enhanced under these conditions, allowing for the synthesis of stress-response proteins. EIF2AK1 is involved in pathways related to erythroid differentiation and heme biosynthesis. Mutations in EIF2AK1 have been linked to certain diseases, although its precise role in human pathology is still under investigation.