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   29-SEP-2021, entry version 152.
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   SMR; Q9UNW9; -.
DR   BioGRID; 110920; 7.
DR   IntAct; Q9UNW9; 3.
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; 164 antibodies.
DR   DNASU; 4858; -.
DR   Ensembl; ENST00000263257; ENSP00000263257; ENSG00000104967.
DR   GeneID; 4858; -.
DR   KEGG; hsa:4858; -.
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; MIKHIME; -.
DR   OrthoDB; 1167935at2759; -.
DR   PhylomeDB; Q9UNW9; -.
DR   TreeFam; TF316981; -.
DR   PathwayCommons; Q9UNW9; -.
DR   BioGRID-ORCS; 4858; 1 hit in 1010 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 210 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; Isopeptide bond;
KW   Mental retardation; 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
//