NOVA2_HUMAN
ID NOVA2_HUMAN Reviewed; 492 AA.
AC Q9UNW9; O43267; Q9UEA1;
DT 04-AUG-2003, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-2000, sequence version 1.
DT 03-AUG-2022, entry version 155.
DE RecName: Full=RNA-binding protein Nova-2 {ECO:0000305};
DE AltName: Full=Astrocytic NOVA1-like RNA-binding protein;
DE AltName: Full=Neuro-oncological ventral antigen 2;
GN Name=NOVA2 {ECO:0000312|HGNC:HGNC:7887}; Synonyms=ANOVA, NOVA3;
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]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Brain;
RX PubMed=10735272; DOI=10.1007/s100480050005;
RA Ueki K., Ramaswamy S., Billings S.J., Mohrenweiser H.W., Louis D.N.;
RT "ANOVA, a putative astrocytic RNA binding protein gene that maps to
RT chromosome 19q13.3.";
RL Neurogenetics 1:31-36(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=9789075; DOI=10.1073/pnas.95.22.13254;
RA Yang Y.Y., Yin G.L., Darnell R.B.;
RT "The neuronal RNA-binding protein Nova-2 is implicated as the autoantigen
RT targeted in POMA patients with dementia.";
RL Proc. Natl. Acad. Sci. U.S.A. 95:13254-13259(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057824; DOI=10.1038/nature02399;
RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E.,
RA Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A.,
RA Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S.,
RA Carrano A.V., Caoile C., Chan Y.M., Christensen M., Cleland C.A.,
RA Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J.,
RA Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M.,
RA Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W.,
RA Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V.,
RA Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D.,
RA McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I.,
RA Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L.,
RA Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A.,
RA She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M.,
RA Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J.,
RA Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E.,
RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M.,
RA Rubin E.M., Lucas S.M.;
RT "The DNA sequence and biology of human chromosome 19.";
RL Nature 428:529-535(2004).
RN [4]
RP FUNCTION.
RX PubMed=10811881; DOI=10.1073/pnas.090553997;
RA Jensen K.B., Musunuru K., Lewis H.A., Burley S.K., Darnell R.B.;
RT "The tetranucleotide UCAY directs the specific recognition of RNA by the
RT Nova K-homology 3 domain.";
RL Proc. Natl. Acad. Sci. U.S.A. 97:5740-5745(2000).
RN [5]
RP SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-112, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=28112733; DOI=10.1038/nsmb.3366;
RA Hendriks I.A., Lyon D., Young C., Jensen L.J., Vertegaal A.C.,
RA Nielsen M.L.;
RT "Site-specific mapping of the human SUMO proteome reveals co-modification
RT with phosphorylation.";
RL Nat. Struct. Mol. Biol. 24:325-336(2017).
RN [6]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 405-480.
RX PubMed=10368286; DOI=10.1016/s0969-2126(99)80025-2;
RA Lewis H.A., Chen H., Edo C., Buckanovich R.J., Yang Y.Y.-L., Musunuru K.,
RA Zhong R., Darnell R.B., Burley S.K.;
RT "Crystal structures of Nova-1 and Nova-2 K-homology RNA-binding domains.";
RL Structure 7:191-203(1999).
RN [7]
RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 405-491 IN COMPLEX WITH RNA.
RX PubMed=10676814; DOI=10.1016/s0092-8674(00)80668-6;
RA Lewis H.A., Musunuru K., Jensen K.B., Edo C., Chen H., Darnell R.B.,
RA Burley S.K.;
RT "Sequence-specific RNA binding by a Nova KH domain: implications for
RT paraneoplastic disease and the fragile X syndrome.";
RL Cell 100:323-332(2000).
RN [8]
RP INVOLVEMENT IN NEDASB, FUNCTION, AND MUTAGENESIS OF 231-TYR--GLY-492.
RX PubMed=32197073; DOI=10.1016/j.ajhg.2020.02.013;
RA Mattioli F., Hayot G., Drouot N., Isidor B., Courraud J., Hinckelmann M.V.,
RA Mau-Them F.T., Sellier C., Goldman A., Telegrafi A., Boughton A.,
RA Gamble C., Moutton S., Quartier A., Jean N., Van Ness P., Grotto S.,
RA Nambot S., Douglas G., Si Y.C., Chelly J., Shad Z., Kaplan E., Dineen R.,
RA Golzio C., Charlet-Berguerand N., Mandel J.L., Piton A.;
RT "De Novo Frameshift Variants in the Neuronal Splicing Factor NOVA2 Result
RT in a Common C-Terminal Extension and Cause a Severe Form of
RT Neurodevelopmental Disorder.";
RL Am. J. Hum. Genet. 106:438-452(2020).
CC -!- FUNCTION: Functions to regulate alternative splicing in neurons by
CC binding pre-mRNA in a sequence-specific manner to activate exon
CC inclusion or exclusion (PubMed:32197073). It binds specifically to the
CC sequences 5'-YCAY-3' and regulates splicing in only a subset of
CC regulated exons (PubMed:10811881). Binding to an exonic 5'-YCAY-3'
CC cluster changes the protein complexes assembled on pre-mRNA, blocking
CC U1 snRNP binding and exon inclusion, whereas binding to an intronic 5'-
CC YCAY-3' cluster enhances spliceosome assembly and exon inclusion. With
CC NOVA1, they perform unique biological functions in different brain
CC areas and cell types. Uniquely regulates alternative splicing events of
CC a series of axon guidance related genes during cortical development,
CC being essential for central nervous system development by regulating
CC neural networks wiring. Regulates differentially alternative splicing
CC on the same transcripts expressed in different neurons. This includes
CC functional differences in transcripts expressed in cortical and
CC cerebellar excitatory versus inhibitory neurons where is required for,
CC respectively, development of laminar structure and motor coordination
CC and synapse formation. Also the regulation the regulation of intron
CC retention can sequester the trans-acting splicing factor PTBP2, acting
CC as a variable cis-acting scaffolding platform for PTBP2 across various
CC natural conditions (By similarity). {ECO:0000250|UniProtKB:A0A1W2P872,
CC ECO:0000269|PubMed:10811881, ECO:0000269|PubMed:32197073}.
CC -!- SUBUNIT: Interacts with PTBP2; the interaction is direct.
CC {ECO:0000250|UniProtKB:A0A1W2P872}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250|UniProtKB:A0A1W2P872}.
CC -!- TISSUE SPECIFICITY: Brain. Expression restricted to astrocytes.
CC -!- DOMAIN: The third KH domain (KH3) recognizes specifically 5'-YCAY-3'.
CC {ECO:0000269|PubMed:10811881}.
CC -!- DISEASE: Neurodevelopmental disorder with or without autistic features
CC and/or structural brain abnormalities (NEDASB) [MIM:618859]: An early-
CC onset neurodevelopmental disorder characterized by intellectual
CC disability, motor and speech delay, autistic features, hypotonia,
CC feeding difficulties, spasticity or ataxic gait, and structural brain
CC abnormalities including cerebral atrophy, cerebellar atrophy, and/or
CC thin corpus callosum. {ECO:0000269|PubMed:32197073}. Note=The disease
CC is caused by variants affecting the gene represented in this entry.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAB88661.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR EMBL; U70477; AAB88661.1; ALT_INIT; mRNA.
DR EMBL; AF083898; AAC72355.1; -; mRNA.
DR EMBL; AC006540; AAD13116.1; -; Genomic_DNA.
DR CCDS; CCDS12679.1; -.
DR RefSeq; NP_002507.1; NM_002516.3.
DR PDB; 1DTJ; X-ray; 2.00 A; A/B/C/D=406-480.
DR PDB; 1EC6; X-ray; 2.40 A; A/B=406-491.
DR PDBsum; 1DTJ; -.
DR PDBsum; 1EC6; -.
DR AlphaFoldDB; Q9UNW9; -.
DR SMR; Q9UNW9; -.
DR BioGRID; 110920; 11.
DR IntAct; Q9UNW9; 3.
DR MINT; Q9UNW9; -.
DR STRING; 9606.ENSP00000263257; -.
DR iPTMnet; Q9UNW9; -.
DR PhosphoSitePlus; Q9UNW9; -.
DR BioMuta; NOVA2; -.
DR DMDM; 33516944; -.
DR EPD; Q9UNW9; -.
DR jPOST; Q9UNW9; -.
DR MassIVE; Q9UNW9; -.
DR MaxQB; Q9UNW9; -.
DR PaxDb; Q9UNW9; -.
DR PeptideAtlas; Q9UNW9; -.
DR PRIDE; Q9UNW9; -.
DR ProteomicsDB; 85338; -.
DR Antibodypedia; 18063; 167 antibodies from 25 providers.
DR DNASU; 4858; -.
DR Ensembl; ENST00000263257.6; ENSP00000263257.4; ENSG00000104967.8.
DR GeneID; 4858; -.
DR KEGG; hsa:4858; -.
DR MANE-Select; ENST00000263257.6; ENSP00000263257.4; NM_002516.4; NP_002507.1.
DR UCSC; uc002pdv.3; human.
DR CTD; 4858; -.
DR DisGeNET; 4858; -.
DR GeneCards; NOVA2; -.
DR HGNC; HGNC:7887; NOVA2.
DR HPA; ENSG00000104967; Tissue enhanced (brain).
DR MalaCards; NOVA2; -.
DR MIM; 601991; gene.
DR MIM; 618859; phenotype.
DR neXtProt; NX_Q9UNW9; -.
DR OpenTargets; ENSG00000104967; -.
DR PharmGKB; PA31689; -.
DR VEuPathDB; HostDB:ENSG00000104967; -.
DR eggNOG; KOG2191; Eukaryota.
DR GeneTree; ENSGT00940000161740; -.
DR HOGENOM; CLU_022670_1_1_1; -.
DR InParanoid; Q9UNW9; -.
DR OMA; QNRALKG; -.
DR OrthoDB; 1167935at2759; -.
DR PhylomeDB; Q9UNW9; -.
DR TreeFam; TF316981; -.
DR PathwayCommons; Q9UNW9; -.
DR SignaLink; Q9UNW9; -.
DR BioGRID-ORCS; 4858; 9 hits in 1070 CRISPR screens.
DR EvolutionaryTrace; Q9UNW9; -.
DR GenomeRNAi; 4858; -.
DR Pharos; Q9UNW9; Tbio.
DR PRO; PR:Q9UNW9; -.
DR Proteomes; UP000005640; Chromosome 19.
DR RNAct; Q9UNW9; protein.
DR Bgee; ENSG00000104967; Expressed in cortical plate and 165 other tissues.
DR ExpressionAtlas; Q9UNW9; baseline and differential.
DR Genevisible; Q9UNW9; HS.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR GO; GO:0003729; F:mRNA binding; ISS:UniProtKB.
DR GO; GO:0003723; F:RNA binding; IDA:UniProtKB.
DR GO; GO:1990825; F:sequence-specific mRNA binding; IDA:UniProtKB.
DR GO; GO:0021954; P:central nervous system neuron development; ISS:UniProtKB.
DR GO; GO:0000398; P:mRNA splicing, via spliceosome; IBA:GO_Central.
DR GO; GO:0120163; P:negative regulation of cold-induced thermogenesis; ISS:YuBioLab.
DR GO; GO:0030182; P:neuron differentiation; IMP:UniProtKB.
DR GO; GO:0000381; P:regulation of alternative mRNA splicing, via spliceosome; IMP:UniProtKB.
DR GO; GO:1902667; P:regulation of axon guidance; ISS:UniProtKB.
DR GO; GO:0010468; P:regulation of gene expression; IBA:GO_Central.
DR GO; GO:0051252; P:regulation of RNA metabolic process; IMP:UniProtKB.
DR Gene3D; 3.30.1370.10; -; 3.
DR InterPro; IPR004087; KH_dom.
DR InterPro; IPR004088; KH_dom_type_1.
DR InterPro; IPR036612; KH_dom_type_1_sf.
DR InterPro; IPR033087; Nova-2.
DR PANTHER; PTHR10288:SF162; PTHR10288:SF162; 1.
DR Pfam; PF00013; KH_1; 3.
DR SMART; SM00322; KH; 3.
DR SUPFAM; SSF54791; SSF54791; 3.
DR PROSITE; PS50084; KH_TYPE_1; 3.
PE 1: Evidence at protein level;
KW 3D-structure; Autism spectrum disorder; Intellectual disability;
KW Isopeptide bond; mRNA processing; mRNA splicing; Neurogenesis; Nucleus;
KW Reference proteome; Repeat; RNA-binding; Ubl conjugation.
FT CHAIN 1..492
FT /note="RNA-binding protein Nova-2"
FT /id="PRO_0000050119"
FT DOMAIN 32..99
FT /note="KH 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00117"
FT DOMAIN 130..196
FT /note="KH 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00117"
FT DOMAIN 406..473
FT /note="KH 3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00117"
FT MOTIF 10..26
FT /note="Bipartite nuclear localization signal"
FT /evidence="ECO:0000255"
FT CROSSLNK 112
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0007744|PubMed:28112733"
FT MUTAGEN 231..492
FT /note="Missing: Loss of alternative splicing regulation."
FT /evidence="ECO:0000269|PubMed:32197073"
FT CONFLICT 247
FT /note="A -> R (in Ref. 1; AAB88661)"
FT /evidence="ECO:0000305"
FT CONFLICT 265..267
FT /note="PAA -> TAT (in Ref. 1; AAB88661)"
FT /evidence="ECO:0000305"
FT STRAND 407..414
FT /evidence="ECO:0007829|PDB:1DTJ"
FT TURN 415..417
FT /evidence="ECO:0007829|PDB:1DTJ"
FT HELIX 418..422
FT /evidence="ECO:0007829|PDB:1DTJ"
FT HELIX 424..426
FT /evidence="ECO:0007829|PDB:1EC6"
FT HELIX 427..436
FT /evidence="ECO:0007829|PDB:1DTJ"
FT STRAND 439..442
FT /evidence="ECO:0007829|PDB:1DTJ"
FT STRAND 454..462
FT /evidence="ECO:0007829|PDB:1DTJ"
FT HELIX 463..476
FT /evidence="ECO:0007829|PDB:1DTJ"
SQ SEQUENCE 492 AA; 49009 MW; 41B63EAF6899256B CRC64;
MEPEAPDSRK RPLETPPEVV CTKRSNTGEE GEYFLKVLIP SYAAGSIIGK GGQTIVQLQK
ETGATIKLSK SKDFYPGTTE RVCLVQGTAE ALNAVHSFIA EKVREIPQAM TKPEVVNILQ
PQTTMNPDRA KQAKLIVPNS TAGLIIGKGG ATVKAVMEQS GAWVQLSQKP EGINLQERVV
TVSGEPEQVH KAVSAIVQKV QEDPQSSSCL NISYANVAGP VANSNPTGSP YASPADVLPA
AAAASAAAAS GLLGPAGLAG VGAFPAALPA FSGTDLLAIS TALNTLASYG YNTNSLGLGL
NSAAASGVLA AVAAGANPAA AAAANLLASY AGEAGAGPAG GAAPPPPPPP GALGSFALAA
AANGYLGAGA GGGAGGGGGP LVAAAAAAGA AGGFLTAEKL AAESAKELVE IAVPENLVGA
ILGKGGKTLV EYQELTGARI QISKKGEFLP GTRNRRVTIT GSPAATQAAQ YLISQRVTYE
QGVRASNPQK VG
