NSUN3_HUMAN
ID NSUN3_HUMAN Reviewed; 340 AA.
AC Q9H649; Q6PG41; Q8IXG9; Q9H6M2;
DT 29-MAY-2007, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2001, sequence version 1.
DT 03-AUG-2022, entry version 134.
DE RecName: Full=tRNA (cytosine(34)-C(5))-methyltransferase, mitochondrial;
DE EC=2.1.1.- {ECO:0000269|PubMed:27214402, ECO:0000269|PubMed:27356879, ECO:0000269|PubMed:27497299};
DE AltName: Full=NOL1/NOP2/Sun domain family member 3 {ECO:0000312|HGNC:HGNC:26208};
GN Name=NSUN3 {ECO:0000312|HGNC:HGNC:26208};
GN ORFNames=MSTP077 {ECO:0000303|Ref.2}, UG0651E06 {ECO:0000303|Ref.4};
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 [LARGE SCALE MRNA].
RC TISSUE=Small intestine;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Aorta;
RA Hui R.T., Sheng H., Qin B.M., Liu Y.Q., Zhao B., Liu B., Wang X.Y.,
RA Zhang Q., Song L., Ji X.J., Liu B.H., Lu H., Xu H.S., Zheng W.Y.,
RA Teng C.Y., Gong Q., Gao R.L.;
RL Submitted (JUL-1999) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT VAL-295.
RC TISSUE=Prostate;
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 NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-156.
RC TISSUE=Fetal brain;
RA Mao Y., Xie Y.;
RT "Isolation of full-length cDNA clones from human fetal brain cDNA
RT library.";
RL Submitted (FEB-2001) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, ACTIVE SITE, AND
RP MUTAGENESIS OF CYS-265.
RX PubMed=27497299; DOI=10.15252/embj.201694885;
RA Haag S., Sloan K.E., Ranjan N., Warda A.S., Kretschmer J., Blessing C.,
RA Huebner B., Seikowski J., Dennerlein S., Rehling P., Rodnina M.V.,
RA Hoebartner C., Bohnsack M.T.;
RT "NSUN3 and ABH1 modify the wobble position of mt-tRNAMet to expand codon
RT recognition in mitochondrial translation.";
RL EMBO J. 35:2104-2119(2016).
RN [6]
RP FUNCTION, CATALYTIC ACTIVITY, AND SUBCELLULAR LOCATION.
RX PubMed=27214402; DOI=10.1038/nchembio.2099;
RA Nakano S., Suzuki T., Kawarada L., Iwata H., Asano K., Suzuki T.;
RT "NSUN3 methylase initiates 5-formylcytidine biogenesis in human
RT mitochondrial tRNA(Met).";
RL Nat. Chem. Biol. 12:546-551(2016).
RN [7]
RP FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, INVOLVEMENT IN COXPD48,
RP VARIANT COXPD48 99-ARG--TRP-340 DEL, AND MUTAGENESIS OF CYS-214.
RX PubMed=27356879; DOI=10.1038/ncomms12039;
RA Van Haute L., Dietmann S., Kremer L., Hussain S., Pearce S.F., Powell C.A.,
RA Rorbach J., Lantaff R., Blanco S., Sauer S., Kotzaeridou U., Hoffmann G.F.,
RA Memari Y., Kolb-Kokocinski A., Durbin R., Mayr J.A., Frye M., Prokisch H.,
RA Minczuk M.;
RT "Deficient methylation and formylation of mt-tRNA(Met) wobble cytosine in a
RT patient carrying mutations in NSUN3.";
RL Nat. Commun. 7:12039-12039(2016).
RN [8]
RP INVOLVEMENT IN COXPD48, AND VARIANTS COXPD48 PRO-141 AND SER-152.
RX PubMed=32488845; DOI=10.1007/s12031-020-01595-8;
RA Paramasivam A., Meena A.K., Venkatapathi C., Pitceathly R.D.S.,
RA Thangaraj K.;
RT "Novel Biallelic NSUN3 Variants Cause Early-Onset Mitochondrial
RT Encephalomyopathy and Seizures.";
RL J. Mol. Neurosci. 70:1962-1965(2020).
CC -!- FUNCTION: Mitochondrial tRNA methyltransferase that mediates
CC methylation of cytosine to 5-methylcytosine (m5C) at position 34 of mt-
CC tRNA(Met) (PubMed:27497299, PubMed:27214402, PubMed:27356879). mt-
CC tRNA(Met) methylation at cytosine(34) takes place at the wobble
CC position of the anticodon and initiates the formation of 5-
CC formylcytosine (f(5)c) at this position (PubMed:27497299,
CC PubMed:27214402, PubMed:27356879). mt-tRNA(Met) containing the f(5)c
CC modification at the wobble position enables recognition of the AUA
CC codon in addition to the AUG codon, expanding codon recognition in
CC mitochondrial translation (PubMed:27497299, PubMed:27356879).
CC {ECO:0000269|PubMed:27214402, ECO:0000269|PubMed:27356879,
CC ECO:0000269|PubMed:27497299}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=cytidine(34) in mitochondrial tRNA + S-adenosyl-L-methionine =
CC 5-methylcytidine(34) in mitochondrial tRNA + H(+) + S-adenosyl-L-
CC homocysteine; Xref=Rhea:RHEA:53076, Rhea:RHEA-COMP:13451, Rhea:RHEA-
CC COMP:13453, ChEBI:CHEBI:15378, ChEBI:CHEBI:57856, ChEBI:CHEBI:59789,
CC ChEBI:CHEBI:74483, ChEBI:CHEBI:82748;
CC Evidence={ECO:0000269|PubMed:27214402, ECO:0000269|PubMed:27356879,
CC ECO:0000269|PubMed:27497299};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:53077;
CC Evidence={ECO:0000305|PubMed:27497299};
CC -!- SUBCELLULAR LOCATION: Mitochondrion matrix
CC {ECO:0000269|PubMed:27214402, ECO:0000269|PubMed:27356879,
CC ECO:0000269|PubMed:27497299}.
CC -!- DISEASE: Combined oxidative phosphorylation deficiency 48 (COXPD48)
CC [MIM:619012]: An autosomal recessive, mitochondrial encephalomyopathy
CC characterized by global developmental delay, microcephaly, failure to
CC thrive, hypotonia, muscle weakness, external ophthalmoplegia, and
CC seizures. Laboratory studies show metabolic acidosis, increased serum
CC lactate, and combined oxidative phosphorylation deficiency in skeletal
CC muscle. {ECO:0000269|PubMed:27356879, ECO:0000269|PubMed:32488845}.
CC Note=The disease is caused by variants affecting the gene represented
CC in this entry.
CC -!- SIMILARITY: Belongs to the class I-like SAM-binding methyltransferase
CC superfamily. RsmB/NOP family. {ECO:0000255|PROSITE-ProRule:PRU01023}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAN76512.1; Type=Miscellaneous discrepancy; Note=Chimera.; Evidence={ECO:0000305};
CC Sequence=AAQ13600.1; Type=Frameshift; Evidence={ECO:0000305};
CC Sequence=BAB15234.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
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DR EMBL; AK025762; BAB15234.1; ALT_INIT; mRNA.
DR EMBL; AK026262; BAB15417.1; -; mRNA.
DR EMBL; AF169972; AAQ13600.1; ALT_FRAME; mRNA.
DR EMBL; BC020602; AAH20602.1; -; mRNA.
DR EMBL; BC057238; AAH57238.1; -; mRNA.
DR EMBL; AF351612; AAN76512.1; ALT_SEQ; mRNA.
DR CCDS; CCDS2927.1; -.
DR RefSeq; NP_071355.1; NM_022072.4.
DR AlphaFoldDB; Q9H649; -.
DR SMR; Q9H649; -.
DR BioGRID; 121978; 35.
DR IntAct; Q9H649; 7.
DR STRING; 9606.ENSP00000318986; -.
DR iPTMnet; Q9H649; -.
DR PhosphoSitePlus; Q9H649; -.
DR BioMuta; NSUN3; -.
DR DMDM; 74733593; -.
DR EPD; Q9H649; -.
DR MassIVE; Q9H649; -.
DR MaxQB; Q9H649; -.
DR PaxDb; Q9H649; -.
DR PeptideAtlas; Q9H649; -.
DR PRIDE; Q9H649; -.
DR ProteomicsDB; 80957; -.
DR Antibodypedia; 32087; 126 antibodies from 20 providers.
DR DNASU; 63899; -.
DR Ensembl; ENST00000314622.9; ENSP00000318986.4; ENSG00000178694.10.
DR GeneID; 63899; -.
DR KEGG; hsa:63899; -.
DR MANE-Select; ENST00000314622.9; ENSP00000318986.4; NM_022072.5; NP_071355.1.
DR UCSC; uc003drl.2; human.
DR CTD; 63899; -.
DR DisGeNET; 63899; -.
DR GeneCards; NSUN3; -.
DR HGNC; HGNC:26208; NSUN3.
DR HPA; ENSG00000178694; Low tissue specificity.
DR MalaCards; NSUN3; -.
DR MIM; 617491; gene.
DR MIM; 619012; phenotype.
DR neXtProt; NX_Q9H649; -.
DR OpenTargets; ENSG00000178694; -.
DR PharmGKB; PA134961151; -.
DR VEuPathDB; HostDB:ENSG00000178694; -.
DR eggNOG; KOG2198; Eukaryota.
DR GeneTree; ENSGT00940000153665; -.
DR HOGENOM; CLU_041061_1_0_1; -.
DR InParanoid; Q9H649; -.
DR OMA; KAWGPMF; -.
DR OrthoDB; 1239772at2759; -.
DR PhylomeDB; Q9H649; -.
DR TreeFam; TF321304; -.
DR BRENDA; 2.1.1.203; 2681.
DR PathwayCommons; Q9H649; -.
DR SignaLink; Q9H649; -.
DR BioGRID-ORCS; 63899; 12 hits in 1079 CRISPR screens.
DR ChiTaRS; NSUN3; human.
DR GenomeRNAi; 63899; -.
DR Pharos; Q9H649; Tbio.
DR PRO; PR:Q9H649; -.
DR Proteomes; UP000005640; Chromosome 3.
DR RNAct; Q9H649; protein.
DR Bgee; ENSG00000178694; Expressed in sperm and 151 other tissues.
DR ExpressionAtlas; Q9H649; baseline and differential.
DR Genevisible; Q9H649; HS.
DR GO; GO:0005762; C:mitochondrial large ribosomal subunit; IBA:GO_Central.
DR GO; GO:0005759; C:mitochondrial matrix; IDA:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR GO; GO:0008168; F:methyltransferase activity; IBA:GO_Central.
DR GO; GO:0016428; F:tRNA (cytosine-5-)-methyltransferase activity; IDA:UniProtKB.
DR GO; GO:0000049; F:tRNA binding; IEA:UniProtKB-KW.
DR GO; GO:0070129; P:regulation of mitochondrial translation; IMP:UniProtKB.
DR GO; GO:0001510; P:RNA methylation; IBA:GO_Central.
DR GO; GO:0031167; P:rRNA methylation; IBA:GO_Central.
DR GO; GO:0002127; P:tRNA wobble base cytosine methylation; IDA:UniProtKB.
DR Gene3D; 3.40.50.150; -; 1.
DR InterPro; IPR001678; MeTrfase_RsmB/NOP2.
DR InterPro; IPR023267; RCMT.
DR InterPro; IPR029063; SAM-dependent_MTases_sf.
DR PANTHER; PTHR22808; PTHR22808; 1.
DR Pfam; PF01189; Methyltr_RsmB-F; 1.
DR PRINTS; PR02008; RCMTFAMILY.
DR SUPFAM; SSF53335; SSF53335; 1.
DR PROSITE; PS51686; SAM_MT_RSMB_NOP; 1.
PE 1: Evidence at protein level;
KW Disease variant; Methyltransferase; Mitochondrion;
KW Primary mitochondrial disease; Reference proteome; RNA-binding;
KW S-adenosyl-L-methionine; Transferase; tRNA-binding.
FT CHAIN 1..340
FT /note="tRNA (cytosine(34)-C(5))-methyltransferase,
FT mitochondrial"
FT /id="PRO_0000289230"
FT ACT_SITE 265
FT /note="Nucleophile"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01023,
FT ECO:0000305|PubMed:27497299"
FT BINDING 139..145
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01023"
FT BINDING 162
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01023"
FT BINDING 193
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01023"
FT BINDING 211
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01023"
FT VARIANT 99..340
FT /note="Missing (in COXPD48)"
FT /evidence="ECO:0000269|PubMed:27356879"
FT /id="VAR_077445"
FT VARIANT 141
FT /note="A -> P (in COXPD48; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:32488845"
FT /id="VAR_085049"
FT VARIANT 152
FT /note="C -> S (in COXPD48; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:32488845"
FT /id="VAR_085050"
FT VARIANT 295
FT /note="A -> V (in dbSNP:rs17854922)"
FT /evidence="ECO:0000269|PubMed:15489334"
FT /id="VAR_032605"
FT MUTAGEN 214
FT /note="C->A: In C2A; catalytic mutant. Abolishes ability to
FT methylate mt-tRNA(Met)."
FT /evidence="ECO:0000269|PubMed:27356879"
FT MUTAGEN 265
FT /note="C->A: Catalytic mutant. Abolishes ability to
FT methylate mt-tRNA(Met)."
FT /evidence="ECO:0000269|PubMed:27497299"
SQ SEQUENCE 340 AA; 38244 MW; 7E09AF2E477EB6F3 CRC64;
MLTQLKAKSE GKLAKQICKV VLDHFEKQYS KELGDAWNTV REILTSPSCW QYAVLLNRFN
YPFELEKDLH LKGYHTLSQG SLPNYPKSVK CYLSRTPGRI PSERHQIGNL KKYYLLNAAS
LLPVLALELR DGEKVLDLCA APGGKSIALL QCACPGYLHC NEYDSLRLRW LRQTLESFIP
QPLINVIKVS ELDGRKMGDA QPEMFDKVLV DAPCSNDRSW LFSSDSQKAS CRISQRRNLP
LLQIELLRSA IKALRPGGIL VYSTCTLSKA ENQDVISEIL NSHGNIMPMD IKGIARTCSH
DFTFAPTGQE CGLLVIPDKG KAWGPMYVAK LKKSWSTGKW
