ARC_HUMAN
ID ARC_HUMAN Reviewed; 396 AA.
AC Q7LC44; Q9UJW6; Q9Y469;
DT 23-JAN-2007, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2004, sequence version 1.
DT 03-AUG-2022, entry version 138.
DE RecName: Full=Activity-regulated cytoskeleton-associated protein {ECO:0000303|PubMed:10970730};
DE Short=hArc {ECO:0000303|PubMed:25748042};
DE AltName: Full=Activity-regulated gene 3.1 protein homolog {ECO:0000250|UniProtKB:Q9WV31};
DE Short=ARC/ARG3.1 {ECO:0000250|UniProtKB:Q9WV31};
DE Short=Arg3.1 {ECO:0000250|UniProtKB:Q9WV31};
GN Name=ARC {ECO:0000303|PubMed:10970730, ECO:0000312|HGNC:HGNC:648};
GN Synonyms=KIAA0278 {ECO:0000303|PubMed:9039502};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1] {ECO:0000312|EMBL:AAF07185.1}
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
RC TISSUE=Forebrain {ECO:0000312|EMBL:AAF07185.1};
RX PubMed=10970730; DOI=10.1006/mcpr.2000.0314;
RA Haug K., Kremerskothen J., Hallmann K., Sander T., Dullinger J., Rau B.,
RA Beyenburg S., Lentze M.J., Barnekow A., Elger C.E., Propping P., Heils A.;
RT "Mutation screening of the chromosome 8q24.3-human activity-regulated
RT cytoskeleton-associated gene (ARC) in idiopathic generalized epilepsy.";
RL Mol. Cell. Probes 14:255-260(2000).
RN [2] {ECO:0000312|EMBL:BAA19667.1}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain {ECO:0000312|EMBL:BAA19667.1};
RX PubMed=9039502; DOI=10.1093/dnares/3.5.321;
RA Nagase T., Seki N., Ishikawa K., Ohira M., Kawarabayasi Y., Ohara O.,
RA Tanaka A., Kotani H., Miyajima N., Nomura N.;
RT "Prediction of the coding sequences of unidentified human genes. VI. The
RT coding sequences of 80 new genes (KIAA0201-KIAA0280) deduced by analysis of
RT cDNA clones from cell line KG-1 and brain.";
RL DNA Res. 3:321-329(1996).
RN [3] {ECO:0000312|EMBL:AAH12321.1}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain {ECO:0000312|EMBL:AAH75802.1}, and
RC Uterus {ECO:0000312|EMBL:AAH12321.1};
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP SUBCELLULAR LOCATION.
RX PubMed=21834987; DOI=10.1186/1741-7007-9-54;
RA Bai S.W., Herrera-Abreu M.T., Rohn J.L., Racine V., Tajadura V.,
RA Suryavanshi N., Bechtel S., Wiemann S., Baum B., Ridley A.J.;
RT "Identification and characterization of a set of conserved and new
RT regulators of cytoskeletal organisation, cell morphology and migration.";
RL BMC Biol. 9:54-54(2011).
RN [5]
RP SUBUNIT.
RX PubMed=25748042; DOI=10.1042/bj20141446;
RA Myrum C., Baumann A., Bustad H.J., Flydal M.I., Mariaule V., Alvira S.,
RA Cuellar J., Haavik J., Soule J., Valpuesta J.M., Marquez J.A., Martinez A.,
RA Bramham C.R.;
RT "Arc is a flexible modular protein capable of reversible self-
RT oligomerization.";
RL Biochem. J. 468:145-158(2015).
CC -!- FUNCTION: Master regulator of synaptic plasticity that self-assembles
CC into virion-like capsids that encapsulate RNAs and mediate
CC intercellular RNA transfer in the nervous system. ARC protein is
CC released from neurons in extracellular vesicles that mediate the
CC transfer of ARC mRNA into new target cells, where ARC mRNA can undergo
CC activity-dependent translation. ARC capsids are endocytosed and are
CC able to transfer ARC mRNA into the cytoplasm of neurons. Acts as a key
CC regulator of synaptic plasticity: required for protein synthesis-
CC dependent forms of long-term potentiation (LTP) and depression (LTD)
CC and for the formation of long-term memory. Regulates synaptic
CC plasticity by promoting endocytosis of AMPA receptors (AMPARs) in
CC response to synaptic activity: this endocytic pathway maintains levels
CC of surface AMPARs in response to chronic changes in neuronal activity
CC through synaptic scaling, thereby contributing to neuronal homeostasis.
CC Acts as a postsynaptic mediator of activity-dependent synapse
CC elimination in the developing cerebellum by mediating elimination of
CC surplus climbing fiber synapses. Accumulates at weaker synapses,
CC probably to prevent their undesired enhancement. This suggests that
CC ARC-containing virion-like capsids may be required to eliminate
CC synaptic material. Required to transduce experience into long-lasting
CC changes in visual cortex plasticity and for long-term memory (By
CC similarity). Involved in postsynaptic trafficking and processing of
CC amyloid-beta A4 (APP) via interaction with PSEN1 (By similarity). In
CC addition to its role in synapses, also involved in the regulation of
CC the immune system: specifically expressed in skin-migratory dendritic
CC cells and regulates fast dendritic cell migration, thereby regulating
CC T-cell activation (By similarity). {ECO:0000250|UniProtKB:Q63053,
CC ECO:0000250|UniProtKB:Q9WV31}.
CC -!- SUBUNIT: Homooligomer; homooligomerizes into virion-like capsids
CC (PubMed:25748042). Interacts with SH3GL1/endophilin-2,
CC SH3GL3/endophilin-3 and DNM2/DYN2 (By similarity). Interacts with
CC CAMK2B (in the kinase inactive state); leading to target ARC to
CC inactive synapses (By similarity). Interacts with PSEN1 (By
CC similarity). {ECO:0000250|UniProtKB:Q63053,
CC ECO:0000250|UniProtKB:Q9WV31, ECO:0000269|PubMed:25748042}.
CC -!- INTERACTION:
CC Q7LC44; Q16527: CSRP2; NbExp=3; IntAct=EBI-750550, EBI-2959737;
CC Q7LC44; P25815: S100P; NbExp=3; IntAct=EBI-750550, EBI-743700;
CC Q7LC44; Q9H788: SH2D4A; NbExp=3; IntAct=EBI-750550, EBI-747035;
CC Q7LC44; O95935: TBX18; NbExp=3; IntAct=EBI-750550, EBI-12085364;
CC -!- SUBCELLULAR LOCATION: Extracellular vesicle membrane
CC {ECO:0000250|UniProtKB:Q63053}; Lipid-anchor
CC {ECO:0000250|UniProtKB:Q9WV31}. Postsynaptic cell membrane
CC {ECO:0000250|UniProtKB:Q9WV31}; Lipid-anchor
CC {ECO:0000250|UniProtKB:Q9WV31}. Synapse {ECO:0000250|UniProtKB:Q63053}.
CC Postsynaptic density {ECO:0000250|UniProtKB:Q63053}. Early endosome
CC membrane {ECO:0000250|UniProtKB:Q63053}. Cell projection, dendrite
CC {ECO:0000250|UniProtKB:Q63053}. Cytoplasm, cytoskeleton
CC {ECO:0000269|PubMed:21834987}. Cytoplasm, cell cortex
CC {ECO:0000250|UniProtKB:Q63053}. Cell projection, dendritic spine
CC {ECO:0000250|UniProtKB:Q63053}. Cytoplasmic vesicle, secretory vesicle,
CC acrosome {ECO:0000250|UniProtKB:Q9WV31}. Note=Forms virion-like
CC extracellular vesicles that are released from neurons. Enriched in
CC postsynaptic density of dendritic spines. Targeted to inactive synapses
CC following interaction with CAMK2B in the kinase inactive state.
CC Accumulation at weaker synapses may be required to prevent their
CC undesired enhancement. Associated with the cell cortex of neuronal soma
CC and dendrites (By similarity). Associated with the sperm tail (By
CC similarity). {ECO:0000250|UniProtKB:Q63053,
CC ECO:0000250|UniProtKB:Q9WV31}.
CC -!- DOMAIN: The protein is evolutionarily related to retrotransposon Gag
CC proteins: it contains large N- and C-terminal domains that form a bi-
CC lobar architecture similar to the capsid domain of human
CC immunodeficiency virus (HIV) gag protein. It contains structural
CC elements found within viral Gag polyproteins originated from the
CC Ty3/gypsy retrotransposon family and retains the ability to form
CC virion-like capsid structures that can mediate mRNA transfer between
CC cells. Tetrapod and fly Arc protein-coding genes originated
CC independently from distinct lineages of Ty3/gypsy retrotransposons.
CC {ECO:0000250|UniProtKB:Q63053}.
CC -!- PTM: Palmitoylation anchors the protein into the membrane by allowing
CC direct insertion into the hydrophobic core of the lipid bilayer.
CC {ECO:0000250|UniProtKB:Q9WV31}.
CC -!- PTM: Ubiquitinated by UBE3A, leading to its degradation by the
CC proteasome, thereby promoting AMPA receptors (AMPARs) expression at
CC synapses. {ECO:0000250|UniProtKB:Q9WV31}.
CC -!- PTM: Phosphorylation at Ser-260 by CaMK2 prevents homooligomerization
CC into virion-like capsids by disrupting an interaction surface essential
CC for high-order oligomerization. Phosphorylation by CaMK2 inhibits
CC synaptic activity. {ECO:0000250|UniProtKB:Q9WV31}.
CC -!- SIMILARITY: Belongs to the ARC/ARG3.1 family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAA19667.1; Type=Erroneous initiation; Evidence={ECO:0000305};
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DR EMBL; AF193421; AAF07185.1; -; mRNA.
DR EMBL; AF248637; AAG33705.1; -; Genomic_DNA.
DR EMBL; D87468; BAA19667.1; ALT_INIT; mRNA.
DR EMBL; BC012321; AAH12321.1; -; mRNA.
DR EMBL; BC075802; AAH75802.1; -; mRNA.
DR CCDS; CCDS34950.1; -.
DR RefSeq; NP_056008.1; NM_015193.4.
DR PDB; 6TN7; X-ray; 1.67 A; B=277-370.
DR PDB; 6TNQ; X-ray; 1.30 A; A/C/E=207-277.
DR PDB; 6TQ0; X-ray; 1.95 A; A/C/E/G/I/K/M/O=207-277.
DR PDB; 6YTU; X-ray; 0.95 A; A/B=99-132.
DR PDBsum; 6TN7; -.
DR PDBsum; 6TNQ; -.
DR PDBsum; 6TQ0; -.
DR PDBsum; 6YTU; -.
DR AlphaFoldDB; Q7LC44; -.
DR SMR; Q7LC44; -.
DR BioGRID; 116842; 23.
DR DIP; DIP-60107N; -.
DR IntAct; Q7LC44; 12.
DR MINT; Q7LC44; -.
DR STRING; 9606.ENSP00000349022; -.
DR iPTMnet; Q7LC44; -.
DR PhosphoSitePlus; Q7LC44; -.
DR BioMuta; ARC; -.
DR DMDM; 74738627; -.
DR MassIVE; Q7LC44; -.
DR PaxDb; Q7LC44; -.
DR PeptideAtlas; Q7LC44; -.
DR PRIDE; Q7LC44; -.
DR ProteomicsDB; 68851; -.
DR Antibodypedia; 3992; 302 antibodies from 34 providers.
DR DNASU; 23237; -.
DR Ensembl; ENST00000356613.4; ENSP00000349022.2; ENSG00000198576.4.
DR GeneID; 23237; -.
DR KEGG; hsa:23237; -.
DR MANE-Select; ENST00000356613.4; ENSP00000349022.2; NM_015193.5; NP_056008.1.
DR UCSC; uc003ywn.2; human.
DR CTD; 23237; -.
DR DisGeNET; 23237; -.
DR GeneCards; ARC; -.
DR HGNC; HGNC:648; ARC.
DR HPA; ENSG00000198576; Tissue enriched (brain).
DR MIM; 612461; gene.
DR neXtProt; NX_Q7LC44; -.
DR OpenTargets; ENSG00000198576; -.
DR PharmGKB; PA24930; -.
DR VEuPathDB; HostDB:ENSG00000198576; -.
DR eggNOG; ENOG502QSPT; Eukaryota.
DR GeneTree; ENSGT00390000003914; -.
DR HOGENOM; CLU_782004_0_0_1; -.
DR InParanoid; Q7LC44; -.
DR OMA; AKKWWEY; -.
DR OrthoDB; 904267at2759; -.
DR PhylomeDB; Q7LC44; -.
DR TreeFam; TF335604; -.
DR PathwayCommons; Q7LC44; -.
DR Reactome; R-HSA-9031628; NGF-stimulated transcription.
DR SignaLink; Q7LC44; -.
DR BioGRID-ORCS; 23237; 10 hits in 1066 CRISPR screens.
DR GenomeRNAi; 23237; -.
DR Pharos; Q7LC44; Tbio.
DR PRO; PR:Q7LC44; -.
DR Proteomes; UP000005640; Chromosome 8.
DR RNAct; Q7LC44; protein.
DR Bgee; ENSG00000198576; Expressed in adenohypophysis and 108 other tissues.
DR Genevisible; Q7LC44; HS.
DR GO; GO:0001669; C:acrosomal vesicle; IEA:UniProtKB-SubCell.
DR GO; GO:0015629; C:actin cytoskeleton; IBA:GO_Central.
DR GO; GO:0070161; C:anchoring junction; IEA:UniProtKB-KW.
DR GO; GO:0005938; C:cell cortex; IEA:UniProtKB-SubCell.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0043197; C:dendritic spine; ISS:UniProtKB.
DR GO; GO:0031901; C:early endosome membrane; IEA:UniProtKB-SubCell.
DR GO; GO:1903561; C:extracellular vesicle; ISS:UniProtKB.
DR GO; GO:0098978; C:glutamatergic synapse; IEA:Ensembl.
DR GO; GO:0045121; C:membrane raft; ISS:UniProtKB.
DR GO; GO:0043025; C:neuronal cell body; TAS:ARUK-UCL.
DR GO; GO:0071598; C:neuronal ribonucleoprotein granule; IEA:Ensembl.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0098839; C:postsynaptic density membrane; IEA:Ensembl.
DR GO; GO:0098845; C:postsynaptic endosome; IEA:Ensembl.
DR GO; GO:0003729; F:mRNA binding; ISS:UniProtKB.
DR GO; GO:0009952; P:anterior/posterior pattern specification; IEA:Ensembl.
DR GO; GO:0016477; P:cell migration; IMP:UniProtKB.
DR GO; GO:0007010; P:cytoskeleton organization; IMP:UniProtKB.
DR GO; GO:0060997; P:dendritic spine morphogenesis; TAS:ARUK-UCL.
DR GO; GO:0006897; P:endocytosis; IEA:UniProtKB-KW.
DR GO; GO:0007492; P:endoderm development; IEA:Ensembl.
DR GO; GO:0007612; P:learning; IEA:Ensembl.
DR GO; GO:0007616; P:long-term memory; ISS:UniProtKB.
DR GO; GO:0060291; P:long-term synaptic potentiation; TAS:ARUK-UCL.
DR GO; GO:0050804; P:modulation of chemical synaptic transmission; ISS:UniProtKB.
DR GO; GO:0051028; P:mRNA transport; ISS:UniProtKB.
DR GO; GO:2000969; P:positive regulation of AMPA receptor activity; IBA:GO_Central.
DR GO; GO:0051260; P:protein homooligomerization; ISS:UniProtKB.
DR GO; GO:0022604; P:regulation of cell morphogenesis; IMP:UniProtKB.
DR GO; GO:0061001; P:regulation of dendritic spine morphogenesis; ISS:ARUK-UCL.
DR GO; GO:1900452; P:regulation of long-term synaptic depression; ISS:UniProtKB.
DR GO; GO:1900271; P:regulation of long-term synaptic potentiation; ISS:UniProtKB.
DR GO; GO:0048168; P:regulation of neuronal synaptic plasticity; IBA:GO_Central.
DR GO; GO:0099149; P:regulation of postsynaptic neurotransmitter receptor internalization; IEA:Ensembl.
DR GO; GO:0110077; P:vesicle-mediated intercellular transport; ISS:UniProtKB.
DR InterPro; IPR023263; Arc.
DR InterPro; IPR040814; Arc_C.
DR InterPro; IPR045557; Arc_N.
DR PANTHER; PTHR15962; PTHR15962; 1.
DR Pfam; PF18162; Arc_C; 1.
DR Pfam; PF19284; Arc_MA; 1.
DR PRINTS; PR02027; ARCARG31.
PE 1: Evidence at protein level;
KW 3D-structure; Cell membrane; Cell projection; Coiled coil; Cytoplasm;
KW Cytoplasmic vesicle; Cytoskeleton; Developmental protein; Endocytosis;
KW Endosome; Lipoprotein; Membrane; Palmitate; Phosphoprotein;
KW Postsynaptic cell membrane; Reference proteome; RNA-binding; Synapse;
KW Transport; Ubl conjugation.
FT CHAIN 1..396
FT /note="Activity-regulated cytoskeleton-associated protein"
FT /id="PRO_0000273285"
FT REGION 89..100
FT /note="Interaction with SH3GL1 or SH3GL3"
FT /evidence="ECO:0000250|UniProtKB:Q63053"
FT REGION 195..214
FT /note="Interaction with DNM2"
FT /evidence="ECO:0000250|UniProtKB:Q63053"
FT REGION 356..396
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COILED 54..78
FT /evidence="ECO:0000255"
FT COMPBIAS 380..396
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 260
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9WV31"
FT MOD_RES 278
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q9WV31"
FT HELIX 100..130
FT /evidence="ECO:0007829|PDB:6YTU"
FT TURN 207..210
FT /evidence="ECO:0007829|PDB:6TNQ"
FT STRAND 212..214
FT /evidence="ECO:0007829|PDB:6TNQ"
FT HELIX 217..231
FT /evidence="ECO:0007829|PDB:6TNQ"
FT HELIX 235..241
FT /evidence="ECO:0007829|PDB:6TNQ"
FT HELIX 242..245
FT /evidence="ECO:0007829|PDB:6TNQ"
FT HELIX 249..257
FT /evidence="ECO:0007829|PDB:6TNQ"
FT HELIX 258..260
FT /evidence="ECO:0007829|PDB:6TNQ"
FT HELIX 264..276
FT /evidence="ECO:0007829|PDB:6TNQ"
FT HELIX 281..288
FT /evidence="ECO:0007829|PDB:6TN7"
FT HELIX 298..312
FT /evidence="ECO:0007829|PDB:6TN7"
FT HELIX 318..327
FT /evidence="ECO:0007829|PDB:6TN7"
FT HELIX 331..337
FT /evidence="ECO:0007829|PDB:6TN7"
FT TURN 338..340
FT /evidence="ECO:0007829|PDB:6TN7"
FT HELIX 345..363
FT /evidence="ECO:0007829|PDB:6TN7"
SQ SEQUENCE 396 AA; 45316 MW; D5C8A8A07FE9615D CRC64;
MELDHRTSGG LHAYPGPRGG QVAKPNVILQ IGKCRAEMLE HVRRTHRHLL AEVSKQVERE
LKGLHRSVGK LESNLDGYVP TSDSQRWKKS IKACLCRCQE TIANLERWVK REMHVWREVF
YRLERWADRL ESTGGKYPVG SESARHTVSV GVGGPESYCH EADGYDYTVS PYAITPPPAA
GELPGQEPAE AQQYQPWVPG EDGQPSPGVD TQIFEDPREF LSHLEEYLRQ VGGSEEYWLS
QIQNHMNGPA KKWWEFKQGS VKNWVEFKKE FLQYSEGTLS REAIQRELDL PQKQGEPLDQ
FLWRKRDLYQ TLYVDADEEE IIQYVVGTLQ PKLKRFLRHP LPKTLEQLIQ RGMEVQDDLE
QAAEPAGPHL PVEDEAETLT PAPNSESVAS DRTQPE
