Q9QZ05

EV SS
Gene name
Eif2ak4 (Gcn2, Kiaa1338)
Protein name
eIF-2-alpha kinase GCN2
Names
Eukaryotic translation initiation factor 2-alpha kinase 4, GCN2-like protein, mGCN2
Species
Mus musculus (Mouse)
KEGG Pathway
mmu:27103
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 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.
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)

1068-1380 (HisRS-like domain) SS

Target domain

589-1000 (Protein kinase domain)

Relief mechanism

Ligand binding, Partner binding

Assay

1493-1648 (C-terminal domain, CTD) EV

Target domain

589-1000 (Protein kinase domain)

Relief mechanism

Partner binding

Assay

Deletion assay, Structural analysis, Mutagenesis experiment

129-255 (charged linker) EV

Target domain

589-1000 (Protein kinase domain)

Relief mechanism

Partner binding

Assay

Deletion assay

Accessory elements

863-871 (Activation loop from InterPro)

Target domain

589-1000 (Protein kinase domain)

Relief mechanism

Assay

874-882 (Activation loop from InterPro)

Target domain

589-1000 (Protein kinase domain)

Relief mechanism

Assay

894-905 (Activation loop from InterPro)

Target domain

589-1000 (Protein kinase domain)

Relief mechanism

Assay

References

Autoinhibited structure

Activated structure

3 structures for Q9QZ05

Entry ID Method Resolution Chain Position Source
1UKX NMR - A 17-139 PDB
4OTN X-ray 190 A A/B 1514-1648 PDB
AF-Q9QZ05-F1 Predicted AlphaFoldDB

No variants for Q9QZ05

Variant ID(s) Position Change Description Diseaes Association Provenance
No variants for Q9QZ05

No associated diseases with Q9QZ05

No regional properties for Q9QZ05

Type Name Position InterPro Accession
No domain, repeats, and functional sites for Q9QZ05

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
cytosol The part of the cytoplasm that does not contain organelles but which does contain other particulate matter, such as protein complexes.
cytosolic ribosome A ribosome located in the cytosol.
polysome A multiribosomal structure representing a linear array of ribosomes held together by messenger RNA. They represent the active complexes in cellular protein synthesis and are able to incorporate amino acids into polypeptides both in vivo and in vitro.

6 GO annotations of molecular function

Name Definition
ATP binding Binding to ATP, adenosine 5'-triphosphate, a universally important coenzyme and enzyme regulator.
eukaryotic initiation factor eIF2 binding Binding to eukaryotic initiation factor eIF2, a protein complex involved in the initiation of ribosome-mediated translation.
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.

36 GO annotations of biological process

Name Definition
adaptive immune response An immune response mediated by cells expressing specific receptors for antigens produced through a somatic diversification process, and allowing for an enhanced secondary response to subsequent exposures to the same antigen (immunological memory).
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 leucine 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 leucine.
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.
defense response to virus Reactions triggered in response to the presence of a virus that act to protect the cell or organism.
DNA damage checkpoint signaling A signal transduction process that contributes to a DNA damage checkpoint.
eiF2alpha phosphorylation in response to endoplasmic reticulum stress The addition of a phosphate group on to the translation initiation factor eIF2alpha, as a result of endoplasmic reticulum stress.
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 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 autophosphorylation The phosphorylation by a protein of one or more of its own amino acid residues (cis-autophosphorylation), or residues on an identical protein (trans-autophosphorylation).
protein phosphorylation The process of introducing a phosphate group on to a protein.
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.

4 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
P47810 Wee1 Wee1-like protein kinase Mus musculus (Mouse) PR
D4A7V9 Eif2ak4 eIF-2-alpha kinase GCN2 Rattus norvegicus (Rat) SS
10 20 30 40 50 60
MAGGRGASGR GRAEPQESYS QRQDHELQAL EAIYGSDFQD LRPDARGRVR EPPEINLVLY
70 80 90 100 110 120
PQGLAGEEVY VQVELQVKCP PTYPDVVPEI ELKNAKGLSN ESVNLLKSHL EELAKKQCGE
130 140 150 160 170 180
VMIFELAHHV QSFLSEHNKP PPKSFHEEML ERQAQEKQQR LLEARRKEEQ EQREILHEIQ
190 200 210 220 230 240
RRKEEIKEEK KRKEMAKQER LEITSLTNQD YASKRDPAGH RAAAILHGGS PDFVGNGKAR
250 260 270 280 290 300
TYSSGRSRRE RQYSVCSGEP SPGSCDILHF SVGSPDQLMV HKGRCVGSDE QLGKVVYNAL
310 320 330 340 350 360
ETATGSFVLL HEWVLQWQKM GPCLTSQEKE KIDKCKRQIQ GAETEFSSLV KLSHPNIVRY
370 380 390 400 410 420
FAMNSREEED SIVIDILAEH VSGISLATHL SHSGPVPAHQ LRKYTAQLLA GLDYLHSNSV
430 440 450 460 470 480
VHKVLSASSV LVDAEGTVKI TDYSISKRLA DICKEDVFEQ ARVRFSDSAL PYKTGKKGDV
490 500 510 520 530 540
WRLGLLLLSL SQGQECGEYP VTIPSDLPAD FQDFLKKCVC LDDKERWSPQ QLLKHSFINP
550 560 570 580 590 600
QPKLPLVEQS PEDSGGQDYI ETVIPSNQLP SAAFFSETQK QFSRYFIEFE ELQLLGKGAF
610 620 630 640 650 660
GAVIKVQNKL DGCCYAVKRI PINPASRHFR RIKGEVTLLS RLHHENIVRY YNAWIERHER
670 680 690 700 710 720
PAVPGTPPPD CTPQAQDSPA TCGKTSGDTE ELGSVEAAAP PPILSSSVEW STSAERSTST
730 740 750 760 770 780
RFPVTGQDSS SDEEDEDERD GVFSQSFLPA SDSDSDIIFD NEDENSKSQN QDEDCNQKDG
790 800 810 820 830 840
SHEIEPSVTA EAVHYLYIQM EYCEKSTLRD TIDQGLFRDT SRLWRLFREI LDGLAYIHEK
850 860 870 880 890 900
GMIHRDLKPV NIFLDSDDHV KIGDFGLATD HLAFTAEGKQ DDQAGDGVIK SDPSGHLTGM
910 920 930 940 950 960
VGTALYVSPE VQGSTKSAYN QKVDLFSLGI IFFEMSYHPM VTASERIFVL NQLRDPTSPK
970 980 990 1000 1010 1020
FPDDFDDGEH TKQKSVISWL LNHDPAKRPT AMELLKSELL PPPQMEESEL HEVLHHTLAN
1030 1040 1050 1060 1070 1080
IDGKAYRTMM SQIFCQHISP AIDYTYDSDI LKGNFLIRTA KIQQLVCETI VRVFKRHGAV
1090 1100 1110 1120 1130 1140
QLCTPLLLPR NRQIYEHNEA ALFMDHSGML VMLPFDLRVP FARYVARNNI LNLKRYCIER
1150 1160 1170 1180 1190 1200
VFRPRKLDRF HPKELLECAF DIVTSTTNSS LPTAETIYTI YEIIQEFPAL QERNYSIYLN
1210 1220 1230 1240 1250 1260
HTMLLKAILL HCGIPEDKLS QVYVILYDAV TEKLTRREVE AKFCNLSLSS NSLCRLYKFI
1270 1280 1290 1300 1310 1320
EQKGDLQDLT PTINSLIKQK TGVAQLVKYS LKDLEDVVGL LKKLGVKLQV SINLGLVYKV
1330 1340 1350 1360 1370 1380
QQHTGIIFQF LAFSKRRQRV VPEILAAGGR YDLLIPKFRG PQTVGPVPTA VGVSIAIDKI
1390 1400 1410 1420 1430 1440
FAAVLNMEEP VTVSSCDLLV VSVGQMSMSR AINLTQKLWT AGITAEIMYD WSQSQEELQE
1450 1460 1470 1480 1490 1500
YCRHHEITYV ALVSDKEGSH VKVKSFEKER QTEKRVLESD LVDHVMQKLR TKVGDERNFR
1510 1520 1530 1540 1550 1560
DASDNLAVQT LKGSFSNASG LFEIHGTTVV PNVIVLAPEK LSASTRRRHE IQVQTRLQTT
1570 1580 1590 1600 1610 1620
LANLHQKSSE IEILAVDLPK ETILQFLSLE WDADEQAFNT TVKQLLSRLP KQRYLKLVCD
1630 1640
EIYNIKVEKK VSVLFLYSYR DDYYRILF