YTHD2_DANRE
ID YTHD2_DANRE Reviewed; 613 AA.
AC E7F1H9; Q7ZUS8;
DT 12-APR-2017, integrated into UniProtKB/Swiss-Prot.
DT 08-MAR-2011, sequence version 1.
DT 03-AUG-2022, entry version 69.
DE RecName: Full=YTH domain-containing family protein 2 {ECO:0000305};
GN Name=ythdf2 {ECO:0000303|PubMed:28192787,
GN ECO:0000312|ZFIN:ZDB-GENE-040426-948};
OS Danio rerio (Zebrafish) (Brachydanio rerio).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Actinopterygii; Neopterygii; Teleostei; Ostariophysi; Cypriniformes;
OC Danionidae; Danioninae; Danio.
OX NCBI_TaxID=7955;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Tuebingen;
RX PubMed=23594743; DOI=10.1038/nature12111;
RA Howe K., Clark M.D., Torroja C.F., Torrance J., Berthelot C., Muffato M.,
RA Collins J.E., Humphray S., McLaren K., Matthews L., McLaren S., Sealy I.,
RA Caccamo M., Churcher C., Scott C., Barrett J.C., Koch R., Rauch G.J.,
RA White S., Chow W., Kilian B., Quintais L.T., Guerra-Assuncao J.A., Zhou Y.,
RA Gu Y., Yen J., Vogel J.H., Eyre T., Redmond S., Banerjee R., Chi J., Fu B.,
RA Langley E., Maguire S.F., Laird G.K., Lloyd D., Kenyon E., Donaldson S.,
RA Sehra H., Almeida-King J., Loveland J., Trevanion S., Jones M., Quail M.,
RA Willey D., Hunt A., Burton J., Sims S., McLay K., Plumb B., Davis J.,
RA Clee C., Oliver K., Clark R., Riddle C., Elliot D., Threadgold G.,
RA Harden G., Ware D., Begum S., Mortimore B., Kerry G., Heath P.,
RA Phillimore B., Tracey A., Corby N., Dunn M., Johnson C., Wood J., Clark S.,
RA Pelan S., Griffiths G., Smith M., Glithero R., Howden P., Barker N.,
RA Lloyd C., Stevens C., Harley J., Holt K., Panagiotidis G., Lovell J.,
RA Beasley H., Henderson C., Gordon D., Auger K., Wright D., Collins J.,
RA Raisen C., Dyer L., Leung K., Robertson L., Ambridge K., Leongamornlert D.,
RA McGuire S., Gilderthorp R., Griffiths C., Manthravadi D., Nichol S.,
RA Barker G., Whitehead S., Kay M., Brown J., Murnane C., Gray E.,
RA Humphries M., Sycamore N., Barker D., Saunders D., Wallis J., Babbage A.,
RA Hammond S., Mashreghi-Mohammadi M., Barr L., Martin S., Wray P.,
RA Ellington A., Matthews N., Ellwood M., Woodmansey R., Clark G., Cooper J.,
RA Tromans A., Grafham D., Skuce C., Pandian R., Andrews R., Harrison E.,
RA Kimberley A., Garnett J., Fosker N., Hall R., Garner P., Kelly D., Bird C.,
RA Palmer S., Gehring I., Berger A., Dooley C.M., Ersan-Urun Z., Eser C.,
RA Geiger H., Geisler M., Karotki L., Kirn A., Konantz J., Konantz M.,
RA Oberlander M., Rudolph-Geiger S., Teucke M., Lanz C., Raddatz G.,
RA Osoegawa K., Zhu B., Rapp A., Widaa S., Langford C., Yang F.,
RA Schuster S.C., Carter N.P., Harrow J., Ning Z., Herrero J., Searle S.M.,
RA Enright A., Geisler R., Plasterk R.H., Lee C., Westerfield M.,
RA de Jong P.J., Zon L.I., Postlethwait J.H., Nusslein-Volhard C.,
RA Hubbard T.J., Roest Crollius H., Rogers J., Stemple D.L.;
RT "The zebrafish reference genome sequence and its relationship to the human
RT genome.";
RL Nature 496:498-503(2013).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RG NIH - Zebrafish Gene Collection (ZGC) project;
RL Submitted (MAR-2003) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP FUNCTION, DISRUPTION PHENOTYPE, AND DEVELOPMENTAL STAGE.
RX PubMed=28192787; DOI=10.1038/nature21355;
RA Zhao B.S., Wang X., Beadell A.V., Lu Z., Shi H., Kuuspalu A., Ho R.K.,
RA He C.;
RT "m(6)A-dependent maternal mRNA clearance facilitates zebrafish maternal-to-
RT zygotic transition.";
RL Nature 542:475-478(2017).
RN [4]
RP FUNCTION, AND MUTAGENESIS OF TRP-445; TRP-499 AND TRP-504.
RX PubMed=28869969; DOI=10.1038/nature23883;
RA Zhang C., Chen Y., Sun B., Wang L., Yang Y., Ma D., Lv J., Heng J.,
RA Ding Y., Xue Y., Lu X., Xiao W., Yang Y.G., Liu F.;
RT "m(6)A modulates haematopoietic stem and progenitor cell specification.";
RL Nature 549:273-276(2017).
CC -!- FUNCTION: Specifically recognizes and binds N6-methyladenosine (m6A)-
CC containing RNAs, and regulates their stability (PubMed:28192787). M6A
CC is a modification present at internal sites of mRNAs and some non-
CC coding RNAs and plays a role in mRNA stability and processing (By
CC similarity). Acts as a regulator of mRNA stability by promoting
CC degradation of m6A-containing mRNAs (By similarity). The YTHDF paralogs
CC (ythdf1, ythdf2 and ythdf3) share m6A-containing mRNAs targets and act
CC redundantly to mediate mRNA degradation and cellular differentiation
CC (By similarity). Plays a key role in maternal-to-zygotic transition
CC during early embryonic development, the process during which maternally
CC inherited mRNAs are degraded: acts by binding m6A-containing maternal
CC mRNAs and promoting their degradation (PubMed:28192787). More than one-
CC third of maternal mRNAs can be modified by m6A (PubMed:28192787).
CC Binding to m6A-containing mRNAs results in mRNA degradation (By
CC similarity). Also involved in hematopoietic stem cells specification by
CC binding to m6A-containing mRNAs, such as notch1a, and promote their
CC degradation (PubMed:28869969). The decreased Notch signaling following
CC notch1a degradation promotes endothelial to hematopoietic transition
CC (PubMed:28869969). Promotes formation of phase-separated membraneless
CC compartments, such as P-bodies or stress granules, by undergoing
CC liquid-liquid phase separation upon binding to mRNAs containing
CC multiple m6A-modified residues: polymethylated mRNAs act as a
CC multivalent scaffold for the binding of YTHDF proteins, juxtaposing
CC their disordered regions and thereby leading to phase separation (By
CC similarity). The resulting mRNA-YTHDF complexes then partition into
CC different endogenous phase-separated membraneless compartments, such as
CC P-bodies, stress granules or neuronal RNA granules (By similarity).
CC {ECO:0000250|UniProtKB:Q9Y5A9, ECO:0000269|PubMed:28192787,
CC ECO:0000269|PubMed:28869969}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol
CC {ECO:0000250|UniProtKB:Q9Y5A9}. Cytoplasm, P-body
CC {ECO:0000250|UniProtKB:Q9Y5A9}. Cytoplasm, Stress granule
CC {ECO:0000250|UniProtKB:Q9Y5A9}. Nucleus {ECO:0000250|UniProtKB:Q9Y5A9}.
CC Note=Localizes to the cytosol and relocates to the nucleus following
CC heat shock stress. Can partition into different structures: into P-
CC bodies in unstressed cells, and into stress granules during stress.
CC {ECO:0000250|UniProtKB:Q9Y5A9}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=E7F1H9-1; Sequence=Displayed;
CC Name=2;
CC IsoId=E7F1H9-2; Sequence=VSP_058906, VSP_058907;
CC -!- DEVELOPMENTAL STAGE: Ubiquitously expressed throughout early
CC embryogenesis. {ECO:0000269|PubMed:28192787}.
CC -!- DOMAIN: The disordered regions have the ability to interact with each
CC other and to 'phase separate' into liquid droplets within the cytosol
CC following binding to mRNAs containing multiple m6A-modified residues.
CC This leads to the partition of m6A-containing mRNAs into membraneless
CC compartments, where mRNAs may be stored, degraded or used to transport
CC mRNAs to dendritic arbors in neurons. {ECO:0000250|UniProtKB:Q9Y5A9}.
CC -!- DISRUPTION PHENOTYPE: Homozygous mutants from the first generation do
CC not show any visible phenotype. Crossing homozygotes mutants together
CC leads to lethality in around 70% of their progeny, because embryos do
CC not developed past the one-cell stage. This lethality is probably
CC mediated by defective sperm males. Defects are due to impaired decay of
CC N6-methyladenosine (m6A)-modified maternal mRNAs, leading to impede
CC zygotic genome activation. Embryos fail to initiate timely maternal-to-
CC zygotic, undergo cell-cycle pause and remain developmentally delayed.
CC {ECO:0000269|PubMed:28192787}.
CC -!- SIMILARITY: Belongs to the YTHDF family. YTHDF2 subfamily.
CC {ECO:0000305}.
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DR EMBL; FP015965; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; FP017274; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC047846; AAH47846.1; -; mRNA.
DR RefSeq; NP_956544.1; NM_200250.1.
DR RefSeq; XP_005158820.1; XM_005158763.3. [E7F1H9-1]
DR AlphaFoldDB; E7F1H9; -.
DR SMR; E7F1H9; -.
DR STRING; 7955.ENSDARP00000107692; -.
DR PaxDb; E7F1H9; -.
DR PeptideAtlas; E7F1H9; -.
DR PRIDE; E7F1H9; -.
DR Ensembl; ENSDART00000127043; ENSDARP00000107692; ENSDARG00000014498. [E7F1H9-1]
DR GeneID; 393220; -.
DR KEGG; dre:393220; -.
DR CTD; 51441; -.
DR ZFIN; ZDB-GENE-040426-948; ythdf2.
DR eggNOG; KOG1901; Eukaryota.
DR GeneTree; ENSGT00940000156761; -.
DR HOGENOM; CLU_022715_0_0_1; -.
DR InParanoid; E7F1H9; -.
DR OMA; RTNGFGD; -.
DR OrthoDB; 1523251at2759; -.
DR PhylomeDB; E7F1H9; -.
DR TreeFam; TF323736; -.
DR PRO; PR:E7F1H9; -.
DR Proteomes; UP000000437; Genome assembly.
DR Proteomes; UP000814640; Chromosome 17.
DR Bgee; ENSDARG00000014498; Expressed in gastrula and 27 other tissues.
DR ExpressionAtlas; E7F1H9; baseline and differential.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0010494; C:cytoplasmic stress granule; ISS:UniProtKB.
DR GO; GO:0005829; C:cytosol; IEA:UniProtKB-SubCell.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0000932; C:P-body; ISS:UniProtKB.
DR GO; GO:0062153; F:C5-methylcytidine-containing RNA binding; ISS:UniProtKB.
DR GO; GO:0003729; F:mRNA binding; IBA:GO_Central.
DR GO; GO:1990247; F:N6-methyladenosine-containing RNA binding; IDA:UniProtKB.
DR GO; GO:0048598; P:embryonic morphogenesis; IMP:UniProtKB.
DR GO; GO:0098508; P:endothelial to hematopoietic transition; IMP:UniProtKB.
DR GO; GO:0007276; P:gamete generation; ISS:UniProtKB.
DR GO; GO:0071425; P:hematopoietic stem cell proliferation; IMP:ZFIN.
DR GO; GO:0006402; P:mRNA catabolic process; IMP:ZFIN.
DR GO; GO:0061157; P:mRNA destabilization; IDA:UniProtKB.
DR GO; GO:0045746; P:negative regulation of Notch signaling pathway; IMP:UniProtKB.
DR GO; GO:2000737; P:negative regulation of stem cell differentiation; ISS:UniProtKB.
DR GO; GO:0060339; P:negative regulation of type I interferon-mediated signaling pathway; ISS:UniProtKB.
DR GO; GO:0001556; P:oocyte maturation; ISS:UniProtKB.
DR GO; GO:0070925; P:organelle assembly; ISS:UniProtKB.
DR GO; GO:0030155; P:regulation of cell adhesion; ISS:UniProtKB.
DR GO; GO:1902036; P:regulation of hematopoietic stem cell differentiation; IMP:UniProtKB.
DR GO; GO:1903538; P:regulation of meiotic cell cycle process involved in oocyte maturation; ISS:UniProtKB.
DR GO; GO:0050767; P:regulation of neurogenesis; ISS:UniProtKB.
DR GO; GO:2000232; P:regulation of rRNA processing; ISS:UniProtKB.
DR GO; GO:0006401; P:RNA catabolic process; IMP:ZFIN.
DR GO; GO:0007284; P:spermatogonial cell division; ISS:UniProtKB.
DR GO; GO:0034063; P:stress granule assembly; ISS:UniProtKB.
DR InterPro; IPR007275; YTH_domain.
DR InterPro; IPR045168; YTH_prot.
DR PANTHER; PTHR12357; PTHR12357; 1.
DR Pfam; PF04146; YTH; 1.
DR PROSITE; PS50882; YTH; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Cytoplasm; Nucleus; Reference proteome; RNA-binding.
FT CHAIN 1..613
FT /note="YTH domain-containing family protein 2"
FT /id="PRO_0000439648"
FT DOMAIN 423..557
FT /note="YTH"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00225"
FT REGION 1..43
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 2..397
FT /note="Localization to mRNA processing bodies (P-bodies)"
FT /evidence="ECO:0000250|UniProtKB:Q9Y5A9"
FT REGION 215..234
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 244..396
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 398..613
FT /note="Interaction with m6A-containing mRNAs"
FT /evidence="ECO:0000250|UniProtKB:Q9Y5A9"
FT REGION 578..613
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1..27
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 283..309
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 338..353
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 589..603
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 429..431
FT /ligand="RNA"
FT /ligand_id="ChEBI:CHEBI:33697"
FT /ligand_part="N(6)-methyladenosine 5'-phosphate residue"
FT /ligand_part_id="ChEBI:CHEBI:74449"
FT /evidence="ECO:0000250|UniProtKB:Q9Y5A9"
FT BINDING 435
FT /ligand="RNA"
FT /ligand_id="ChEBI:CHEBI:33697"
FT /ligand_part="N(6)-methyladenosine 5'-phosphate residue"
FT /ligand_part_id="ChEBI:CHEBI:74449"
FT /evidence="ECO:0000250|UniProtKB:Q9Y5A9"
FT BINDING 445..446
FT /ligand="RNA"
FT /ligand_id="ChEBI:CHEBI:33697"
FT /ligand_part="N(6)-methyladenosine 5'-phosphate residue"
FT /ligand_part_id="ChEBI:CHEBI:74449"
FT /evidence="ECO:0000305|PubMed:28869969"
FT BINDING 475
FT /ligand="RNA"
FT /ligand_id="ChEBI:CHEBI:33697"
FT /ligand_part="N(6)-methyladenosine 5'-phosphate residue"
FT /ligand_part_id="ChEBI:CHEBI:74449"
FT /evidence="ECO:0000250|UniProtKB:Q9Y5A9"
FT BINDING 499
FT /ligand="RNA"
FT /ligand_id="ChEBI:CHEBI:33697"
FT /ligand_part="N(6)-methyladenosine 5'-phosphate residue"
FT /ligand_part_id="ChEBI:CHEBI:74449"
FT /evidence="ECO:0000305|PubMed:28869969"
FT BINDING 504
FT /ligand="RNA"
FT /ligand_id="ChEBI:CHEBI:33697"
FT /ligand_part="N(6)-methyladenosine 5'-phosphate residue"
FT /ligand_part_id="ChEBI:CHEBI:74449"
FT /evidence="ECO:0000305|PubMed:28869969"
FT VAR_SEQ 587..596
FT /note="EVQGSDPYSN -> TCHGLAPSGI (in isoform 2)"
FT /id="VSP_058906"
FT VAR_SEQ 597..613
FT /note="Missing (in isoform 2)"
FT /id="VSP_058907"
FT MUTAGEN 445
FT /note="W->A: Abolished binding to N6-methyladenosine (m6A)-
FT containing RNAs; when associated to A-499 and A-504."
FT /evidence="ECO:0000269|PubMed:28869969"
FT MUTAGEN 499
FT /note="W->A: Abolished binding to N6-methyladenosine (m6A)-
FT containing RNAs; when associated to A-445 and A-504."
FT /evidence="ECO:0000269|PubMed:28869969"
FT MUTAGEN 504
FT /note="W->A: Abolished binding to N6-methyladenosine (m6A)-
FT containing RNAs; when associated to A-445 and A-499."
FT /evidence="ECO:0000269|PubMed:28869969"
FT CONFLICT 219
FT /note="T -> A (in Ref. 2; AAH47846)"
FT /evidence="ECO:0000305"
FT CONFLICT 354
FT /note="A -> V (in Ref. 2; AAH47846)"
FT /evidence="ECO:0000305"
FT CONFLICT 468
FT /note="L -> P (in Ref. 2; AAH47846)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 613 AA; 66049 MW; FC5CB338C646DDB9 CRC64;
MSASSLLEQR PKGQANKVQN GAVTQKDTLN DDEFEPYLNA QPRQSNAYTA MSDSYMPSYY
SPSIGFTYSL NEAAWSTGGD PPMPYLASYG QLSNGEHHFL PDAMFGQSGA LGNNPFLGQH
GFNFFPSGID FPAWGNSSSQ GQSTQSSGYS SSYAYAPSTL GGAMIDGQSP FAANEPLNKA
VGMNSLDQGM AGLKIGAGDM APKVVGSGLP GGPLSQVSTA PTMPPASMAP AKTASWADIA
SKPAKPQPKL KTKGGLGGTN LPPPPIKHNM DIGTWDNKGN MPKPAAPQQT SLPTNGQPPN
QSSPQPGATA GGVPQLPLSN GQLVPPTGQL VQHPLPPGGQ PGAVPPQLSQ GPPASQPSQP
TRWVPPRNRA NGFGDAAGGP GQSPPNSGMG GITVPAEPHP VLEKLRMVNN YNPKDFDWNP
KHGRVFIIKS YSEDDIHRSI KYNIWCSTEH GNKRLDAAYR SLANKGPLYL LFSVNGSGHF
CGVAEMRSPV DYNTCAGVWS QDKWKGRFDV RWIFVKDVPN SQLRHIRLEN NENKPVTNSR
DTQEVPLDKA RQVLKIIASY KHTTSIFDDF SHYEKRQEEE ESVKKVEVQG SDPYSNNSSR
SHYRMQDRQG RVK
