EIF2AK2

Fig1. Schematic representation of protein regulators of PKR with their interacting interfaces. (Charles Bou-Nader, 2019)

What is EIF2AK2 protein?

EIF2AK2 (eukaryotic translation initiation factor 2 alpha kinase 2) gene is a protein coding gene which situated on the short arm of chromosome 2 at locus 2p22. The protein encoded by this gene is a serine/threonine protein kinase that is activated by autophosphorylation after binding to dsRNA. The activated form of the encoded protein can phosphorylate translation initiation factor EIF2S1, which in turn inhibits protein synthesis. This protein is also activated by manganese ions and heparin. The EIF2AK2 protein is consisted of 551 amino acids and its molecular mass is approximately 62.1 kDa.

What is the function of EIF2AK2 protein?

EIF2AK2 is an enzyme that is a member of the protein kinase family. EIF2AK2's primary function is to phosphorylate eukaryotic translation initiation factor 2α (eIF2α), a key regulatory step in protein synthesis. Phosphorylated eIF2α can slow down global protein synthesis, but at the same time enhance the translation of specific stress-response proteins, such as ATF4 (activated transcription factor 4). This unique regulatory role enables EIF2AK2 to play an important role in the response of cells to various stressful conditions, including endoplasmic reticulum stress, nutritional deficiencies, and viral infections. In this way, EIF2AK2 helps maintain cell homeostasis and adapt to environmental changes.

EIF2AK2 Related Signaling Pathway

EIF2AK2, also known as PKR, is an important protein kinase that is involved in regulating a variety of cell signaling pathways. It activates its kinase activity by sensing double-stranded RNA (dsRNA) within the cell, which is a common intermediate during viral replication. Once activated, EIF2AK2/PKR phosphorylates eukaryotic translation initiation factor 2α (eIF2α), leading to a decrease in global protein synthesis while promoting the translation of specific mrnas, such as those encoding antiviral response proteins. In addition, EIF2AK2/PKR can also respond to other types of cellular stress, such as endoplasmic reticulum stress, apoptotic signaling, and some metabolic disorders.

EIF2AK2 Related Diseases

The EIF2AK2 protein has been linked to a variety of diseases, most notably diabetes, obesity, and insulin resistance. Genetic studies have found that certain variants of the EIF2AK2 gene are associated with an increased risk of these metabolic diseases. In addition to metabolic diseases, abnormal activity of EIF2AK2 may also be associated with other diseases, such as neurodegenerative diseases, certain cancers, and cardiovascular diseases.

Bioapplications of EIF2AK2

The main application of EIF2AK2 protein is currently in the field of biomedical research as a potential therapeutic target to explore the treatment of a variety of diseases, including viral infections, cancer, neurodegeneration, and metabolic disorders.

Case study 1: Yapei Li, 2018

Endothelial cell senescence is regarded as a vital characteristic of cardiovascular diseases. Elevated palmitate (PA) is an independent risk factor of cardiovascular diseases, but its role in endothelial cell senescence is currently unknown. During the course of studying the prosenescent role of PA, the researchers discovered a key role of dsRNA-dependent protein kinase [protein kinase R (PKR)] in endothelial senescence. Exposure of human umbilical vein endothelial cells (HUVECs) to PA-induced cell senescence is characterized by increased levels of senescence-associated β-galactose glucosidase activity, excessive production of reactive oxygen species production, impaired cellular proliferation, and G1 phase arrest. This phenomenon is associated with an increase of PKR autophosphorylation and decreased activity of sirtuin 1 (Sirt1), a pivotal antisenescent factor. PKR inactivation by PKR siRNA or its phosphorylation inhibitor 2-aminopurine significantly attenuated PA-induced HUVEC senescence by reversing Sirt1 activity and its downstream signaling. Moreover, to study the regulatory mechanism between PKR and Sirt1, we found that PKR promotes JNK activation to inhibit Sirt1 activity and that this effect could be reversed by the JNK inhibitor SP600125.

Fig1. HUVECs were incubated with PA at different doses (0, 100, 200, or 400 μM) for 16 h and the intracellular protein expression of phosphorylated (p)-PKR, PKR, and Sirt1 were measured by Western blot (left).

Fig2. dsRNA-dependent protein kinase [protein kinase R (PKR)] inhibition relieves palmitate (PA)-induced human umbilical vein endothelial cell (HUVEC) senescence.

Case study 2: Die Wang, 2017

The central role of protein kinases in controlling disease processes has spurred efforts to develop pharmaceutical regulators of their activity. A rational strategy to achieve this end is to determine intrinsic auto-regulatory processes, then selectively target these different states of kinases to repress their activation. Here the researchers investigate auto-regulation of the innate immune effector protein kinase R, which phosphorylates the eukaryotic initiation factor 2α to inhibit global protein translation.

They demonstrate that protein kinase R activity is controlled by auto-inhibition via an intra-molecular interaction. Part of this mechanism of control had previously been reported, but was then controverted. They account for the discrepancy and extend our understanding of the auto-inhibitory mechanism by identifying that auto-inhibition is paradoxically instigated by incipient auto-phosphorylation. Phosphor-residues at the amino-terminus instigate an intra-molecular interaction that enlists both of the N-terminal RNA-binding motifs of the protein with separate surfaces of the C-terminal kinase domain, to co-operatively inhibit kinase activation.

Fig3. The indicated recombinant PKR proteins electrophoretically separated by their isoelectric point (pI), then visualized with the Coomassie brilliant blue stain.

Fig4. Absorption resonance curves for ligand coupling of the indicated recombinant PKR proteins, demonstrating that the phosphor-residues generate distinct profiles.

EIF2AK2 has several biochemical functions, for example, ATP binding,double-stranded RNA binding,eukaryotic translation initiation factor 2alpha kinase activity. Some of the functions are cooperated with other proteins, some of the functions could acted by EIF2AK2 itself. We selected most functions EIF2AK2 had, and list some proteins which have the same functions with EIF2AK2. You can find most of the proteins on our site.

EIF2AK2 has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with EIF2AK2 here. Most of them are supplied by our site. Hope this information will be useful for your research of EIF2AK2.

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