D4A7V9

SS
Gene name
Eif2ak4 (Gcn2)
Protein name
eIF-2-alpha kinase GCN2
Names
EC 2.7.11.1 , Eukaryotic translation initiation factor 2-alpha kinase 4 , GCN2-like protein
Species
Rattus norvegicus (Rat)
KEGG Pathway
EC number
2.7.11.1: Protein-serine/threonine kinases
Protein Class

Descriptions

GCN2 (General control non-derepressible protein 2) is an eIF-2α kinase, which phosphorylates eIF-2α in response to low amino acid availability, initiating the integrated stress response (ISR). GCN2 has five conserved folded domains: an N-terminal RWD (RING-finger proteins, WD repeat-containing proteins and the yeast DEAD-like helicases) domain, a pseudokinase domain, a catalytically active kinase domain, a ‘HisRS-like’ domain (named due to sequence similarity to histidyl-tRNA synthetase) and a C-terminal domain (or CTD). In addition to this, there is also is a ‘charged linker’ region, a likely unstructured region found between the RWD and pseudokinase domains. In a basal state (in non-starved cells), GCN2 forms an inactive homodimer, with multiple autoinhibitory interactions occurring between the CTD, the HisRS-like domains and the kinase domains preventing aberrant activation of the kinase. Also, the charged linker region of GCN2, located between RWD and pseudokinase domains, played an additional, smaller role in inhibiting the enzyme. <br> The activation of GCN2 (upon amino acid starvation) is linked to a structural rearrangement and ultimately to a release of these multidomain autoinhibitory contacts, while still maintaining a dimeric structure. Once opened, the kinase domain is free to autophosphorylate two threonine residues in the activation loop of the kinase domain, causing a stabilization the active state.

Autoinhibitory domains (AIDs)

1058-1490 (HisRS-like catalytic domain) SS

Target domain

590-1001 (Protein kinase domain)

Relief mechanism

Ligand binding, Partner binding

Assay

1533-1649 (C-terminal domain, CTD) SS

Target domain

590-1001 (Protein kinase domain)

Relief mechanism

Partner binding

Assay

137-176 (charged linker) SS

Target domain

590-1001 (Protein kinase domain)

Relief mechanism

Partner binding

Assay

Accessory elements

864-883 (Activation loop from InterPro)

Target domain

590-1001 (Protein kinase domain)

Relief mechanism

Assay

895-906 (Activation loop from InterPro)

Target domain

590-1001 (Protein kinase domain)

Relief mechanism

Assay

References

Autoinhibited structure

Activated structure

1 structures for D4A7V9

Entry ID Method Resolution Chain Position Source
AF-D4A7V9-F1 Predicted AlphaFoldDB

No variants for D4A7V9

Variant ID(s) Position Change Description Diseaes Association Provenance
No variants for D4A7V9

No associated diseases with D4A7V9

6 regional properties for D4A7V9

Type Name Position InterPro Accession
domain Peptidase S8/S53 domain 181 - 419 IPR000209
domain Peptidase S8 propeptide/proteinase inhibitor I9 77 - 149 IPR010259
domain Proteinase K-like catalytic domain 156 - 421 IPR034193
domain Proprotein convertase subtilisin/kexin type 9, C-terminal domain 3 602 - 682 IPR041051
domain Proprotein convertase subtilisin/kexin type 9, C-terminal domain 2 535 - 600 IPR041052
domain Proprotein convertase subtilisin/kexin type 9, C-terminal domain 1 450 - 531 IPR041254

Functions

Description
EC Number 2.7.11.1 Protein-serine/threonine kinases
Subcellular Localization
  • Cytoplasm
PANTHER Family
PANTHER Subfamily
PANTHER Protein Class
PANTHER Pathway Category No pathway information available

3 GO annotations of cellular component

Name Definition
cytoplasm The contents of a cell excluding the plasma membrane and nucleus, but including other subcellular structures.
cytosol The part of the cytoplasm that does not contain organelles but which does contain other particulate matter, such as protein complexes.
nucleus A membrane-bounded organelle of eukaryotic cells in which chromosomes are housed and replicated. In most cells, the nucleus contains all of the cell's chromosomes except the organellar chromosomes, and is the site of RNA synthesis and processing. In some species, or in specialized cell types, RNA metabolism or DNA replication may be absent.

5 GO annotations of molecular function

Name Definition
ATP binding Binding to ATP, adenosine 5'-triphosphate, a universally important coenzyme and enzyme regulator.
eukaryotic translation initiation factor 2alpha kinase activity Catalysis of the reaction
protein serine kinase activity Catalysis of the reactions
protein serine/threonine kinase activity Catalysis of the reactions
tRNA binding Binding to a transfer RNA.

33 GO annotations of biological process

Name Definition
cell cycle The progression of biochemical and morphological phases and events that occur in a cell during successive cell replication or nuclear replication events. Canonically, the cell cycle comprises the replication and segregation of genetic material followed by the division of the cell, but in endocycles or syncytial cells nuclear replication or nuclear division may not be followed by cell division.
cellular response to amino acid starvation Any process that results in a change in state or activity of a cell (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of deprivation of amino acids.
cellular response to cold Any process that results in a change in state or activity of a cell (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a cold stimulus, a temperature stimulus below the optimal temperature for that organism.
cellular response to starvation Any process that results in a change in state or activity of a cell (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of deprivation of nourishment.
cellular response to UV Any process that results in a change in state or activity of a cell (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of an ultraviolet radiation (UV light) stimulus. Ultraviolet radiation is electromagnetic radiation with a wavelength in the range of 10 to 380 nanometers.
DNA damage checkpoint signaling A signal transduction process that contributes to a DNA damage checkpoint.
endoplasmic reticulum unfolded protein response The series of molecular signals generated as a consequence of the presence of unfolded proteins in the endoplasmic reticulum (ER) or other ER-related stress; results in changes in the regulation of transcription and translation.
GCN2-mediated signaling A series of reactions in which a signal is passed on to downstream proteins within the cell via GCN2 (also known as EIF2AK4), an intracellular protein kinase that is activated by stress signals, such as amino acid starvation.
learning Any process in an organism in which a relatively long-lasting adaptive behavioral change occurs as the result of experience.
long-term memory The memory process that deals with the storage, retrieval and modification of information a long time (typically weeks, months or years) after receiving that information. This type of memory is typically dependent on gene transcription regulated by second messenger activation.
negative regulation by host of viral genome replication A process in which a host organism stops, prevents or reduces the frequency, rate or extent of viral genome replication.
negative regulation of CREB transcription factor activity Any process that stops, prevents, or reduces the frequency, rate or extent of the activity of the transcription factor CREB.
negative regulation of cytoplasmic translational initiation in response to stress Any process that stops, prevents or reduces the rate of cytoplasmic translation initiation as a result of a stimulus indicating the organism is under stress.
negative regulation of neuron differentiation Any process that stops, prevents, or reduces the frequency, rate or extent of neuron differentiation.
negative regulation of translation Any process that stops, prevents, or reduces the frequency, rate or extent of the chemical reactions and pathways resulting in the formation of proteins by the translation of mRNA or circRNA.
negative regulation of translational initiation Any process that stops, prevents, or reduces the frequency, rate or extent of translational initiation.
negative regulation of translational initiation in response to stress Any process that stops, prevents or reduces the rate of translation initiation as a result of a stimulus indicating the organism is under stress.
neuron projection extension Long distance growth of a single neuron projection involved in cellular development. A neuron projection is a prolongation or process extending from a nerve cell, e.g. an axon or dendrite.
positive regulation of adaptive immune response Any process that activates or increases the frequency, rate, or extent of an adaptive immune response.
positive regulation of defense response to virus by host Any host process that results in the promotion of antiviral immune response mechanisms, thereby limiting viral replication.
positive regulation of gene expression Any process that increases the frequency, rate or extent of gene expression. Gene expression is the process in which a gene's coding sequence is converted into a mature gene product (protein or RNA).
positive regulation of long-term synaptic potentiation Any process that activates or increases the frequency, rate or extent of long-term synaptic potentiation.
positive regulation of protein phosphorylation Any process that activates or increases the frequency, rate or extent of addition of phosphate groups to amino acids within a protein.
positive regulation of translational initiation in response to starvation Any process that activates or increases the frequency, rate or extent of translation initiation, as a result of deprivation of nourishment.
protein phosphorylation The process of introducing a phosphate group on to a protein.
regulation of cytoplasmic translational initiation in response to stress Modulation of the frequency, rate or extent of cytoplasmic translational initiation as a result of a stimulus indicating the organism is under stress. The stress is usually, but not necessarily, exogenous (e.g. temperature, humidity, ionizing radiation).
regulation of feeding behavior Any process that modulates the rate, frequency or extent of the behavior associated with the intake of food.
regulation of translational initiation Any process that modulates the frequency, rate or extent of translational initiation.
regulation of translational initiation by eIF2 alpha phosphorylation Any process that modulates the frequency, rate or extent of translation initiation in response to stress by the phosphorylation of eIF2 alpha.
regulation of translational initiation in response to stress Any process that modulates the frequency, rate or extent of translation initiation, as a result of a stimulus indicating the organism is under stress.
response to endoplasmic reticulum stress Any process that results in a change in state or activity of a cell (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a stress acting at the endoplasmic reticulum. ER stress usually results from the accumulation of unfolded or misfolded proteins in the ER lumen.
T cell activation involved in immune response The change in morphology and behavior of a mature or immature T cell resulting from exposure to a mitogen, cytokine, chemokine, cellular ligand, or an antigen for which it is specific, leading to the initiation or perpetuation of an immune response.
viral translation A process by which viral mRNA is translated into viral protein, using the host cellular machinery.

3 homologous proteins in AiPD

UniProt AC Gene Name Protein Name Species Evidence Code
P15442 GCN2 eIF-2-alpha kinase GCN2 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast) EV
Q9P2K8 EIF2AK4 eIF-2-alpha kinase GCN2 Homo sapiens (Human) EV
Q9QZ05 Eif2ak4 eIF-2-alpha kinase GCN2 Mus musculus (Mouse) EV SS
10 20 30 40 50 60
MAGGRGAAGR GPAEPQESYS QRQDHELQAL EAIYGSDFQD LRPDARGRVR EPPEINLVLY
70 80 90 100 110 120
PQGLAGEEVY VQVELRVKCP PTYPDVVPEI ELKNTKGLSN ESVNLLKSHL EELAKKQCGE
130 140 150 160 170 180
VMIFELAHHV QSFLSEHNKP PPKSFHEEML ERQAQEKQQR LLEARQKEEQ EQREILHEIQ
190 200 210 220 230 240
KRKEEIKEEK KRKEMAKQER LEITSLTNQD HASKRDPAGH RAAAFLHGGS PDFVGNGKAR
250 260 270 280 290 300
AHSSGRSRRE RQYSVCSGEA SPGSCDILYF CVGSADQLMV HKGKCVGSDE QLGKVVYNAL
310 320 330 340 350 360
ETATGSFVLL YEWVLQWQKK MGPCLTSQEK EKIDKCKKQI QGAETEFSSL VKLSHPNIVR
370 380 390 400 410 420
YFAMNSREEK DSIVVDILAE HISGISLAAH LSHSGPVPMH QLRKYTAQLL AGLDYLHRNS
430 440 450 460 470 480
VVHKVLSTAS VLVDAEGTVK ITDYSISKRL ADICKEDVFE QTRVRFSDSA LPYKTGKKGD
490 500 510 520 530 540
VWRLGLLLLS LSQGQECEEY PVTIPSDLPA DFQDFLKKCV CLDDKERWSP QQLLKHSFIN
550 560 570 580 590 600
PQPKMPLVEQ SPEDSGGQDY IETIIPSNQL PSAAFFTETQ RQFSRYFIEF EELQLLGKGA
610 620 630 640 650 660
FGAVIKVQNK LDGCCYAVKR IPINPASRQF RRIKGEVTLL SRLHHENIVR YYNAWIERHE
670 680 690 700 710 720
RPAVPGTPPP DYIPQAQNSS ATGGKASGDT EELGSVEAAA PPPILSSSVE WSTSAERSNS
730 740 750 760 770 780
ARFPVTGQDS SSDEEDEDER DGVFSQSFLP ASDSDSDIIF DNEDENSKSQ NQDEDCNEKD
790 800 810 820 830 840
SRHEIEPSVT TEAVHYLYIQ MEYCEKSTLR DTIDQGLFRD TSRLWRLFRE ILDGLAYIHE
850 860 870 880 890 900
KGMIHRDLKP VNIFLDSDDH VKIGDFGLAT DHLAFNAEGK QDDQAGDHVI KSDPSGHLTG
910 920 930 940 950 960
MVGTALYVSP EVQGSTKSAY NQKVDLFSLG IILFEMSYHP MVTASERIFV LNQLRDPTSP
970 980 990 1000 1010 1020
KFPDDFEDGE HTKQKSVISW LLNHDPAKRP TAMELLKSEL LPPPQMEESE LHEVLHHTLA
1030 1040 1050 1060 1070 1080
NTDGKAYRTM MSQLFCQHSS PAIDYTYDSD ILKGNFLIRT AKIQQLVCET IVRVFKRHGA
1090 1100 1110 1120 1130 1140
VQLCTPLLLP RNRQIYEHNE AALFMDHSGM LVMLPFDLRV PFARYVARNN ILNLKRYCIE
1150 1160 1170 1180 1190 1200
RVFRPRKLDR FHPKELLECA FDIVTSTANS SLPTAETIYT IYEVIQEFPA LQERNYSIYL
1210 1220 1230 1240 1250 1260
NHTMLLKAIL LHCGIPEDKL SQVYVILYDA VTEKLTRREV EAKFCNLSLS SNSLCRLYKF
1270 1280 1290 1300 1310 1320
IEQKGDLQDL TPTINSLIKQ KTGIAQLVKY SLKDLEEVVG LLKKLGVKLQ VSINLGLVYK
1330 1340 1350 1360 1370 1380
VQQHNGIIFQ FLAFSKRRQR VVPEILAAGG RYDLLIPKFR GPQALGPVPT AVGVSIAIDK
1390 1400 1410 1420 1430 1440
IFAAVLNMGE PVTVSSCDLL VVSAGQMSMS RAINLTQKLW TAGITAEIMY DWSQSQEELQ
1450 1460 1470 1480 1490 1500
EYCRHHEITY VALVSDKEGS HVKVKSFEKE RQTEKRVLES DLVDHVMQKL RTKVGDERNF
1510 1520 1530 1540 1550 1560
RDASDNLAVQ TLKGSFSNAS GLFEIHGTTV VPTVSVISPE KLSASTRRRH EIQVQTRLQT
1570 1580 1590 1600 1610 1620
TLANLHQKSS EIEILAVDLP KETILQFLSL EWDADEQAFN TTVKQLLSRL PKQRYLKLVC
1630 1640
DEIYNIKVEK KVSVLFLYSY RDDYYRILF