ATF4_BOVIN
ID ATF4_BOVIN Reviewed; 348 AA.
AC Q3ZCH6;
DT 31-OCT-2006, integrated into UniProtKB/Swiss-Prot.
DT 27-SEP-2005, sequence version 1.
DT 25-MAY-2022, entry version 108.
DE RecName: Full=Cyclic AMP-dependent transcription factor ATF-4 {ECO:0000305};
DE Short=cAMP-dependent transcription factor ATF-4 {ECO:0000305};
DE AltName: Full=Activating transcription factor 4 {ECO:0000303|PubMed:16682973};
GN Name=ATF4 {ECO:0000303|PubMed:16682973};
OS Bos taurus (Bovine).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Ruminantia; Pecora; Bovidae;
OC Bovinae; Bos.
OX NCBI_TaxID=9913;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=Hereford {ECO:0000312|EMBL:AAI02237.1};
RC TISSUE=Mammary gland {ECO:0000312|EMBL:AAI02237.1};
RG NIH - Mammalian Gene Collection (MGC) project;
RL Submitted (AUG-2005) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP INTERACTION WITH CEP290.
RX PubMed=16682973; DOI=10.1038/ng1786;
RA Sayer J.A., Otto E.A., O'toole J.F., Nurnberg G., Kennedy M.A., Becker C.,
RA Hennies H.C., Helou J., Attanasio M., Fausett B.V., Utsch B., Khanna H.,
RA Liu Y., Drummond I., Kawakami I., Kusakabe T., Tsuda M., Ma L., Lee H.,
RA Larson R.G., Allen S.J., Wilkinson C.J., Nigg E.A., Shou C., Lillo C.,
RA Williams D.S., Hoppe B., Kemper M.J., Neuhaus T., Parisi M.A., Glass I.A.,
RA Petry M., Kispert A., Gloy J., Ganner A., Walz G., Zhu X., Goldman D.,
RA Nurnberg P., Swaroop A., Leroux M.R., Hildebrandt F.;
RT "The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and
RT activates transcription factor ATF4.";
RL Nat. Genet. 38:674-681(2006).
CC -!- FUNCTION: Transcription factor that binds the cAMP response element
CC (CRE) (consensus: 5'-GTGACGT[AC][AG]-3') and displays two biological
CC functions, as regulator of metabolic and redox processes under normal
CC cellular conditions, and as master transcription factor during
CC integrated stress response (ISR) (By similarity). Binds to asymmetric
CC CRE's as a heterodimer and to palindromic CRE's as a homodimer (By
CC similarity). Core effector of the ISR, which is required for adaptation
CC to various stress such as endoplasmic reticulum (ER) stress, amino acid
CC starvation, mitochondrial stress or oxidative stress. During ISR, ATF4
CC translation is induced via an alternative ribosome translation re-
CC initiation mechanism in response to EIF2S1/eIF-2-alpha phosphorylation,
CC and stress-induced ATF4 acts as a master transcription factor of
CC stress-responsive genes in order to promote cell recovery (By
CC similarity). Promotes the transcription of genes linked to amino acid
CC sufficiency and resistance to oxidative stress to protect cells against
CC metabolic consequences of ER oxidation (By similarity). Activates the
CC transcription of NLRP1, possibly in concert with other factors in
CC response to ER stress. Activates the transcription of asparagine
CC synthetase (ASNS) in response to amino acid deprivation or ER stress.
CC However, when associated with DDIT3/CHOP, the transcriptional
CC activation of the ASNS gene is inhibited in response to amino acid
CC deprivation (By similarity). Together with DDIT3/CHOP, mediates
CC programmed cell death by promoting the expression of genes involved in
CC cellular amino acid metabolic processes, mRNA translation and the
CC terminal unfolded protein response (terminal UPR), a cellular response
CC that elicits programmed cell death when ER stress is prolonged and
CC unresolved (By similarity). Together with DDIT3/CHOP, activates the
CC transcription of the IRS-regulator TRIB3 and promotes ER stress-induced
CC neuronal cell death by regulating the expression of BBC3/PUMA in
CC response to ER stress. May cooperate with the UPR transcriptional
CC regulator QRICH1 to regulate ER protein homeostasis which is critical
CC for cell viability in response to ER stress (By similarity). In the
CC absence of stress, ATF4 translation is at low levels and it is required
CC for normal metabolic processes such as embryonic lens formation, fetal
CC liver hematopoiesis, bone development and synaptic plasticity (By
CC similarity). Acts as a regulator of osteoblast differentiation in
CC response to phosphorylation by RPS6KA3/RSK2: phosphorylation in
CC osteoblasts enhances transactivation activity and promotes expression
CC of osteoblast-specific genes and post-transcriptionally regulates the
CC synthesis of Type I collagen, the main constituent of the bone matrix
CC (By similarity). Cooperates with FOXO1 in osteoblasts to regulate
CC glucose homeostasis through suppression of beta-cell production and
CC decrease in insulin production. Activates transcription of SIRT4.
CC Regulates the circadian expression of the core clock component PER2 and
CC the serotonin transporter SLC6A4. Binds in a circadian time-dependent
CC manner to the cAMP response elements (CRE) in the SLC6A4 and PER2
CC promoters and periodically activates the transcription of these genes.
CC Mainly acts as a transcriptional activator in cellular stress
CC adaptation, but it can also act as a transcriptional repressor: acts as
CC a regulator of synaptic plasticity by repressing transcription, thereby
CC inhibiting induction and maintenance of long-term memory (By
CC similarity). Regulates synaptic functions via interaction with DISC1 in
CC neurons, which inhibits ATF4 transcription factor activity by
CC disrupting ATF4 dimerization and DNA-binding (By similarity).
CC {ECO:0000250|UniProtKB:P18848, ECO:0000250|UniProtKB:Q06507}.
CC -!- SUBUNIT: Binds DNA as a homodimer and as a heterodimer. Heterodimer;
CC heterodimerizes with CEBPB. Heterodimer; heterodimerizes with
CC DDIT3/CHOP. Interacts with CEP290 (via an N-terminal region)
CC (PubMed:16682973). Interacts with NEK6, DAPK2 (isoform 2) and
CC ZIPK/DAPK3 (By similarity). Interacts (via its leucine zipper domain)
CC with GABBR1 and GABBR2 (via their C-termini) (By similarity). Forms a
CC heterodimer with TXLNG in osteoblasts (By similarity). Interacts (via
CC its DNA binding domain) with FOXO1 (C-terminal half); the interaction
CC occurs in osteoblasts and regulates glucose homeostasis through
CC suppression of beta-cell proliferation and a decrease in insulin
CC production. Interacts with SATB2; the interaction results in enhanced
CC DNA binding and transactivation by these transcription factors (By
CC similarity). Interacts with ABRAXAS2 (By similarity). Interacts with
CC TRIB3, inhibiting the transactivation activity of ATF4. Interacts with
CC DISC1; which inhibits ATF4 transcription factor activity by disrupting
CC ATF4 dimerization and DNA-binding (By similarity). Interacts with
CC EP300/p300; EP300/p300 stabilizes ATF4 and increases its
CC transcriptional activity independently of its catalytic activity by
CC preventing its ubiquitination (By similarity).
CC {ECO:0000250|UniProtKB:P18848, ECO:0000250|UniProtKB:Q06507,
CC ECO:0000250|UniProtKB:Q9ES19, ECO:0000269|PubMed:16682973}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250|UniProtKB:P18848}. Nucleus
CC speckle {ECO:0000250|UniProtKB:P18848}. Cytoplasm
CC {ECO:0000250|UniProtKB:Q9ES19}. Cell membrane
CC {ECO:0000250|UniProtKB:Q9ES19}. Cytoplasm, cytoskeleton, microtubule
CC organizing center, centrosome {ECO:0000250|UniProtKB:P18848}.
CC Note=Colocalizes with GABBR1 in hippocampal neuron dendritic membranes
CC (By similarity). Colocalizes with NEK6 at the centrosome. Recruited to
CC nuclear speckles following interaction with EP300/p300 (By similarity).
CC {ECO:0000250|UniProtKB:P18848, ECO:0000250|UniProtKB:Q9ES19}.
CC -!- DOMAIN: The BetaTrCP degron motif promotes binding to BTRC when
CC phosphorylated. {ECO:0000250|UniProtKB:P18848}.
CC -!- PTM: Ubiquitinated by SCF(BTRC) in response to mTORC1 signal, followed
CC by proteasomal degradation and leading to down-regulate expression of
CC SIRT4. Interaction with EP300/p300 inhibits ubiquitination by
CC SCF(BTRC). {ECO:0000250|UniProtKB:P18848}.
CC -!- PTM: Phosphorylation at Ser-242 by RPS6KA3/RSK2 in osteoblasts enhances
CC transactivation activity and promotes osteoblast differentiation (By
CC similarity). Phosphorylated on the betaTrCP degron motif at Ser-215,
CC followed by phosphorylation at Ser-220, Ser-227, Ser-231 and Ser-245,
CC promoting interaction with BTRC and ubiquitination. Phosphorylation is
CC promoted by mTORC1 (By similarity). Phosphorylation at Ser-211 by CK2
CC decreases its stability. Phosphorylated by NEK6 (By similarity).
CC {ECO:0000250|UniProtKB:P18848, ECO:0000250|UniProtKB:Q06507}.
CC -!- PTM: Hydroxylated by PHD3, leading to decreased protein stability.
CC {ECO:0000250|UniProtKB:P18848}.
CC -!- SIMILARITY: Belongs to the bZIP family. {ECO:0000305}.
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DR EMBL; BC102236; AAI02237.1; -; mRNA.
DR RefSeq; NP_001029514.1; NM_001034342.2.
DR AlphaFoldDB; Q3ZCH6; -.
DR SMR; Q3ZCH6; -.
DR STRING; 9913.ENSBTAP00000023213; -.
DR PaxDb; Q3ZCH6; -.
DR GeneID; 509107; -.
DR KEGG; bta:509107; -.
DR CTD; 468; -.
DR eggNOG; KOG4571; Eukaryota.
DR InParanoid; Q3ZCH6; -.
DR OrthoDB; 1524842at2759; -.
DR Proteomes; UP000009136; Unplaced.
DR GO; GO:1990590; C:ATF1-ATF4 transcription factor complex; IBA:GO_Central.
DR GO; GO:1990589; C:ATF4-CREB1 transcription factor complex; IBA:GO_Central.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005815; C:microtubule organizing center; IEA:UniProtKB-SubCell.
DR GO; GO:0016607; C:nuclear speck; IEA:UniProtKB-SubCell.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0008140; F:cAMP response element binding protein binding; ISS:UniProtKB.
DR GO; GO:0003677; F:DNA binding; ISS:UniProtKB.
DR GO; GO:0001228; F:DNA-binding transcription activator activity, RNA polymerase II-specific; IBA:GO_Central.
DR GO; GO:0003700; F:DNA-binding transcription factor activity; ISS:UniProtKB.
DR GO; GO:0046982; F:protein heterodimerization activity; ISS:UniProtKB.
DR GO; GO:0000978; F:RNA polymerase II cis-regulatory region sequence-specific DNA binding; ISS:UniProtKB.
DR GO; GO:0000977; F:RNA polymerase II transcription regulatory region sequence-specific DNA binding; IBA:GO_Central.
DR GO; GO:0030282; P:bone mineralization; ISS:UniProtKB.
DR GO; GO:0034198; P:cellular response to amino acid starvation; ISS:UniProtKB.
DR GO; GO:0034599; P:cellular response to oxidative stress; ISS:UniProtKB.
DR GO; GO:0032922; P:circadian regulation of gene expression; ISS:UniProtKB.
DR GO; GO:0035162; P:embryonic hemopoiesis; ISS:UniProtKB.
DR GO; GO:0030968; P:endoplasmic reticulum unfolded protein response; ISS:UniProtKB.
DR GO; GO:0140468; P:HRI-mediated signaling; ISS:UniProtKB.
DR GO; GO:0140467; P:integrated stress response signaling; ISS:UniProtKB.
DR GO; GO:0070059; P:intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress; ISS:UniProtKB.
DR GO; GO:0070309; P:lens fiber cell morphogenesis; ISS:UniProtKB.
DR GO; GO:0042789; P:mRNA transcription by RNA polymerase II; ISS:UniProtKB.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; ISS:UniProtKB.
DR GO; GO:0036499; P:PERK-mediated unfolded protein response; ISS:UniProtKB.
DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; ISS:UniProtKB.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; ISS:UniProtKB.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; ISS:UniProtKB.
DR GO; GO:0045667; P:regulation of osteoblast differentiation; ISS:UniProtKB.
DR GO; GO:0048167; P:regulation of synaptic plasticity; ISS:UniProtKB.
DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR GO; GO:0006355; P:regulation of transcription, DNA-templated; ISS:UniProtKB.
DR GO; GO:0034976; P:response to endoplasmic reticulum stress; ISS:UniProtKB.
DR InterPro; IPR029811; ATF4.
DR InterPro; IPR004827; bZIP.
DR InterPro; IPR046347; bZIP_sf.
DR PANTHER; PTHR13044:SF32; PTHR13044:SF32; 1.
DR Pfam; PF00170; bZIP_1; 1.
DR SMART; SM00338; BRLZ; 1.
DR SUPFAM; SSF57959; SSF57959; 1.
DR PROSITE; PS50217; BZIP; 1.
DR PROSITE; PS00036; BZIP_BASIC; 1.
PE 1: Evidence at protein level;
KW Acetylation; Activator; Biological rhythms; Cell membrane; Cytoplasm;
KW Cytoskeleton; DNA-binding; Hydroxylation; Isopeptide bond; Membrane;
KW Nucleus; Phosphoprotein; Reference proteome; Repressor; Transcription;
KW Transcription regulation; Ubl conjugation.
FT CHAIN 1..348
FT /note="Cyclic AMP-dependent transcription factor ATF-4"
FT /id="PRO_0000258021"
FT DOMAIN 275..338
FT /note="bZIP"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00978"
FT REGION 151..174
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 187..265
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 277..297
FT /note="Basic motif"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00978"
FT REGION 302..338
FT /note="Interaction with GABBR1"
FT /evidence="ECO:0000250|UniProtKB:Q9ES19"
FT REGION 303..331
FT /note="Leucine-zipper"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00978"
FT MOTIF 211..220
FT /note="BetaTrCP degron motif"
FT /evidence="ECO:0000250|UniProtKB:P18848"
FT COMPBIAS 216..249
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 211
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P18848"
FT MOD_RES 215
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q06507"
FT MOD_RES 220
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q06507"
FT MOD_RES 227
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q06507"
FT MOD_RES 231
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q06507"
FT MOD_RES 232
FT /note="4-hydroxyproline"
FT /evidence="ECO:0000250|UniProtKB:Q06507"
FT MOD_RES 242
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q06507"
FT MOD_RES 245
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q06507"
FT MOD_RES 308
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P18848"
FT CROSSLNK 53
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0000250|UniProtKB:P18848"
FT CROSSLNK 256
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0000250|UniProtKB:P18848"
FT CROSSLNK 264
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0000250|UniProtKB:P18848"
FT CROSSLNK 269
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0000250|UniProtKB:P18848"
SQ SEQUENCE 348 AA; 38245 MW; 84C13618325BB27E CRC64;
MAEMSFLSSE VLGGDFVSPF DQLGLGAEES LGLLDDNLEV AKHFKHHGFS CDKAKAGSSE
WLAVDWLVSD NSKEDAFSGT DWMVEKMDLK EFDFDILFSK DDLETMPDEL LATLDDTCDL
FQPLVQETNK EPPQIVNPIG HLPEGLPTID QGAPFTFFQP LPPSPGTLSS TPDHSFSLEL
CSEVVIPEGD SKPDSTTTGF PQCIKEEDAP SDNDSGICMS PDSSLGSPQD SPSTSRGSPN
KSLLSPGALS GSSRPKPYDP PGEKMVAAKV KGEKLDKKLK KMEQNKTAAT RYRQKKRAEQ
EALTGECKEL EKKNEALKEK ADSLAKEIQY LKDQIEEVRK AREKKRVL
