SYFM_HUMAN
ID SYFM_HUMAN Reviewed; 451 AA.
AC O95363; B2R664; Q53F66; Q5TCS3; Q6FG29; Q9NPY7; Q9P062;
DT 23-NOV-2004, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-1999, sequence version 1.
DT 03-AUG-2022, entry version 193.
DE RecName: Full=Phenylalanine--tRNA ligase, mitochondrial;
DE EC=6.1.1.20 {ECO:0000269|PubMed:19549855, ECO:0000269|PubMed:22833457};
DE AltName: Full=Phenylalanyl-tRNA synthetase;
DE Short=PheRS;
DE Flags: Precursor;
GN Name=FARS2; Synonyms=FARS1; ORFNames=HSPC320;
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], AND SUBUNIT.
RX PubMed=10329163; DOI=10.1006/jmbi.1999.2708;
RA Bullard J.M., Cai Y.-C., Demeler B., Spremulli L.L.;
RT "Expression and characterization of a human mitochondrial phenylalanyl-tRNA
RT synthetase.";
RL J. Mol. Biol. 288:567-577(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT SER-280.
RC TISSUE=Caudate nucleus;
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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT SER-280.
RA Halleck A., Ebert L., Mkoundinya M., Schick M., Eisenstein S., Neubert P.,
RA Kstrang K., Schatten R., Shen B., Henze S., Mar W., Korn B., Zuo D., Hu Y.,
RA LaBaer J.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Kidney epithelium;
RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.;
RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=14574404; DOI=10.1038/nature02055;
RA Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L.,
RA Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R.,
RA Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D.,
RA Andrews T.D., Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J.,
RA Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H.,
RA Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J.,
RA Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P.,
RA Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V.,
RA Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J.,
RA Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E.,
RA Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J.,
RA French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J.,
RA Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C.,
RA Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A.,
RA Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R.,
RA Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M.,
RA Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K.,
RA Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R.,
RA Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M.,
RA Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A.,
RA Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L.,
RA Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I.,
RA Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y.,
RA Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E.,
RA Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A.,
RA Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W.,
RA Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M.,
RA West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J.,
RA Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M.,
RA Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I.,
RA Rogers J., Beck S.;
RT "The DNA sequence and analysis of human chromosome 6.";
RL Nature 425:805-811(2003).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Pancreas;
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 [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 108-451, AND VARIANT SER-280.
RC TISSUE=Umbilical cord blood;
RA Ye M., Zhang Q.-H., Zhou J., Shen Y., Wu X.-Y., Guan Z.Q., Wang L.,
RA Fan H.-Y., Mao Y.-F., Dai M., Huang Q.-H., Chen S.-J., Chen Z.;
RT "Human partial CDS from CD34+ stem cells.";
RL Submitted (MAY-1999) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-202, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C.,
RA Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [9]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=25944712; DOI=10.1002/pmic.201400617;
RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D.,
RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.;
RT "N-terminome analysis of the human mitochondrial proteome.";
RL Proteomics 15:2519-2524(2015).
RN [10]
RP X-RAY CRYSTALLOGRAPHY (2.20 ANGSTROMS) OF 38-451 IN COMPLEX WITH SUBSTRATE,
RP AND SUBUNIT.
RX PubMed=18611382; DOI=10.1016/j.str.2008.03.020;
RA Klipcan L., Levin I., Kessler N., Moor N., Finarov I., Safro M.;
RT "The tRNA-induced conformational activation of human mitochondrial
RT phenylalanyl-tRNA synthetase.";
RL Structure 16:1095-1104(2008).
RN [11]
RP X-RAY CRYSTALLOGRAPHY (2.60 ANGSTROMS) OF 38-451 IN COMPLEX WITH SUBSTRATE,
RP FUNCTION, CATALYTIC ACTIVITY, SUBSTRATE SPECIFICITY, AND KINETIC
RP PARAMETERS.
RX PubMed=19549855; DOI=10.1073/pnas.0905212106;
RA Klipcan L., Moor N., Kessler N., Safro M.G.;
RT "Eukaryotic cytosolic and mitochondrial phenylalanyl-tRNA synthetases
RT catalyze the charging of tRNA with the meta-tyrosine.";
RL Proc. Natl. Acad. Sci. U.S.A. 106:11045-11048(2009).
RN [12]
RP VARIANTS COXPD14 THR-329 AND VAL-391, CHARACTERIZATION OF VARIANTS COXPD14
RP CYS-144; THR-329 AND VAL-391, FUNCTION, CATALYTIC ACTIVITY, AND KINETIC
RP PARAMETERS.
RX PubMed=22833457; DOI=10.1093/hmg/dds294;
RA Elo J.M., Yadavalli S.S., Euro L., Isohanni P., Gotz A., Carroll C.J.,
RA Valanne L., Alkuraya F.S., Uusimaa J., Paetau A., Caruso E.M., Pihko H.,
RA Ibba M., Tyynismaa H., Suomalainen A.;
RT "Mitochondrial phenylalanyl-tRNA synthetase mutations underlie fatal
RT infantile Alpers encephalopathy.";
RL Hum. Mol. Genet. 21:4521-4529(2012).
RN [13]
RP VARIANT COXPD14 CYS-144.
RX PubMed=22499341; DOI=10.1136/jmedgenet-2012-100836;
RA Shamseldin H.E., Alshammari M., Al-Sheddi T., Salih M.A., Alkhalidi H.,
RA Kentab A., Repetto G.M., Hashem M., Alkuraya F.S.;
RT "Genomic analysis of mitochondrial diseases in a consanguineous population
RT reveals novel candidate disease genes.";
RL J. Med. Genet. 49:234-241(2012).
RN [14]
RP VARIANT SPG77 TYR-142, AND CHARACTERIZATION OF VARIANT SPG77 TYR-142.
RX PubMed=26553276; DOI=10.1002/humu.22930;
RA Yang Y., Liu W., Fang Z., Shi J., Che F., He C., Yao L., Wang E., Wu Y.;
RT "A newly identified missense mutation in FARS2 causes autosomal-recessive
RT spastic paraplegia.";
RL Hum. Mutat. 37:165-169(2016).
CC -!- FUNCTION: Is responsible for the charging of tRNA(Phe) with
CC phenylalanine in mitochondrial translation. To a lesser extent, also
CC catalyzes direct attachment of m-Tyr (an oxidized version of Phe) to
CC tRNA(Phe), thereby opening the way for delivery of the misacylated tRNA
CC to the ribosome and incorporation of ROS-damaged amino acid into
CC proteins. {ECO:0000269|PubMed:19549855, ECO:0000269|PubMed:22833457}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-phenylalanine + tRNA(Phe) = AMP + diphosphate + H(+) +
CC L-phenylalanyl-tRNA(Phe); Xref=Rhea:RHEA:19413, Rhea:RHEA-COMP:9668,
CC Rhea:RHEA-COMP:9699, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:33019, ChEBI:CHEBI:58095, ChEBI:CHEBI:78442,
CC ChEBI:CHEBI:78531, ChEBI:CHEBI:456215; EC=6.1.1.20;
CC Evidence={ECO:0000269|PubMed:19549855, ECO:0000269|PubMed:22833457};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=2.2 uM for L-phenylalanine {ECO:0000269|PubMed:19549855,
CC ECO:0000269|PubMed:22833457};
CC KM=1900 uM for L-tyrosine {ECO:0000269|PubMed:19549855,
CC ECO:0000269|PubMed:22833457};
CC KM=11.7 uM for DL-m-tyrosine {ECO:0000269|PubMed:19549855,
CC ECO:0000269|PubMed:22833457};
CC KM=7.3 uM for L-phenylalanine {ECO:0000269|PubMed:19549855,
CC ECO:0000269|PubMed:22833457};
CC KM=2.9 mM for ATP {ECO:0000269|PubMed:19549855,
CC ECO:0000269|PubMed:22833457};
CC KM=1.2 uM for tRNA(Phe) {ECO:0000269|PubMed:19549855,
CC ECO:0000269|PubMed:22833457};
CC Note=kcat is 2.8 min(-1), 2.0 min(-1) and 3.1 min(-1) with L-
CC phenylalanine, L-tyrosine and m-tyrosine as substrate, respectively.
CC Thus, the catalytic efficiency of the m-Tyr attachment is only 5-fold
CC lower than that of the correct amino acid, while that of Tyr
CC attachment is 1000-fold lower (PubMed:19549855).
CC {ECO:0000269|PubMed:19549855};
CC -!- SUBUNIT: Monomer. {ECO:0000269|PubMed:10329163,
CC ECO:0000269|PubMed:18611382, ECO:0000269|PubMed:19549855}.
CC -!- INTERACTION:
CC O95363; Q6UY14-3: ADAMTSL4; NbExp=3; IntAct=EBI-2513774, EBI-10173507;
CC O95363; Q6RW13: AGTRAP; NbExp=3; IntAct=EBI-2513774, EBI-741181;
CC O95363; Q6RW13-2: AGTRAP; NbExp=3; IntAct=EBI-2513774, EBI-11522760;
CC O95363; Q96IF1: AJUBA; NbExp=3; IntAct=EBI-2513774, EBI-949782;
CC O95363; Q10567-3: AP1B1; NbExp=3; IntAct=EBI-2513774, EBI-11978055;
CC O95363; Q9UKG1: APPL1; NbExp=9; IntAct=EBI-2513774, EBI-741243;
CC O95363; Q9BYV9: BACH2; NbExp=3; IntAct=EBI-2513774, EBI-1642333;
CC O95363; O95429: BAG4; NbExp=3; IntAct=EBI-2513774, EBI-2949658;
CC O95363; Q8N9N5-2: BANP; NbExp=4; IntAct=EBI-2513774, EBI-11524452;
CC O95363; Q5H9J7: BEX5; NbExp=3; IntAct=EBI-2513774, EBI-10243741;
CC O95363; Q13137: CALCOCO2; NbExp=7; IntAct=EBI-2513774, EBI-739580;
CC O95363; Q8NA61-2: CBY2; NbExp=3; IntAct=EBI-2513774, EBI-11524851;
CC O95363; Q4G0S7: CCDC152; NbExp=3; IntAct=EBI-2513774, EBI-18398007;
CC O95363; Q9BXL8: CDCA4; NbExp=3; IntAct=EBI-2513774, EBI-1773949;
CC O95363; Q96DZ9: CMTM5; NbExp=3; IntAct=EBI-2513774, EBI-2548702;
CC O95363; Q96DZ9-2: CMTM5; NbExp=3; IntAct=EBI-2513774, EBI-11522780;
CC O95363; A8MQ03: CYSRT1; NbExp=3; IntAct=EBI-2513774, EBI-3867333;
CC O95363; Q6ZPD8: DGAT2L6; NbExp=3; IntAct=EBI-2513774, EBI-12831978;
CC O95363; Q9BQC3: DPH2; NbExp=3; IntAct=EBI-2513774, EBI-10237931;
CC O95363; Q92997: DVL3; NbExp=3; IntAct=EBI-2513774, EBI-739789;
CC O95363; Q5TD97: FHL5; NbExp=3; IntAct=EBI-2513774, EBI-750641;
CC O95363; Q9Y680: FKBP7; NbExp=3; IntAct=EBI-2513774, EBI-3918971;
CC O95363; A1L4K1: FSD2; NbExp=3; IntAct=EBI-2513774, EBI-5661036;
CC O95363; Q13322-4: GRB10; NbExp=3; IntAct=EBI-2513774, EBI-12353035;
CC O95363; A8MV81: HIGD1C; NbExp=3; IntAct=EBI-2513774, EBI-12809676;
CC O95363; Q6NT76: HMBOX1; NbExp=3; IntAct=EBI-2513774, EBI-2549423;
CC O95363; Q9UKT9: IKZF3; NbExp=6; IntAct=EBI-2513774, EBI-747204;
CC O95363; Q9ULR0-1: ISY1; NbExp=3; IntAct=EBI-2513774, EBI-18398632;
CC O95363; Q9H3M0: KCNF1; NbExp=3; IntAct=EBI-2513774, EBI-6918743;
CC O95363; Q8N5Z5: KCTD17; NbExp=3; IntAct=EBI-2513774, EBI-743960;
CC O95363; A1A4E9: KRT13; NbExp=3; IntAct=EBI-2513774, EBI-10171552;
CC O95363; Q15323: KRT31; NbExp=3; IntAct=EBI-2513774, EBI-948001;
CC O95363; O76011: KRT34; NbExp=3; IntAct=EBI-2513774, EBI-1047093;
CC O95363; Q6A162: KRT40; NbExp=6; IntAct=EBI-2513774, EBI-10171697;
CC O95363; Q07627: KRTAP1-1; NbExp=3; IntAct=EBI-2513774, EBI-11959885;
CC O95363; P60370: KRTAP10-5; NbExp=3; IntAct=EBI-2513774, EBI-10172150;
CC O95363; P60409: KRTAP10-7; NbExp=6; IntAct=EBI-2513774, EBI-10172290;
CC O95363; P60410: KRTAP10-8; NbExp=3; IntAct=EBI-2513774, EBI-10171774;
CC O95363; P60411: KRTAP10-9; NbExp=6; IntAct=EBI-2513774, EBI-10172052;
CC O95363; Q9BYR6: KRTAP3-3; NbExp=3; IntAct=EBI-2513774, EBI-3957694;
CC O95363; Q9NR34: MAN1C1; NbExp=3; IntAct=EBI-2513774, EBI-7260764;
CC O95363; Q99750: MDFI; NbExp=3; IntAct=EBI-2513774, EBI-724076;
CC O95363; Q14696: MESD; NbExp=3; IntAct=EBI-2513774, EBI-6165891;
CC O95363; Q9UJV3-2: MID2; NbExp=6; IntAct=EBI-2513774, EBI-10172526;
CC O95363; Q13064: MKRN3; NbExp=3; IntAct=EBI-2513774, EBI-2340269;
CC O95363; Q6PF18: MORN3; NbExp=3; IntAct=EBI-2513774, EBI-9675802;
CC O95363; Q8NI38: NFKBID; NbExp=3; IntAct=EBI-2513774, EBI-10271199;
CC O95363; Q7Z3S9: NOTCH2NLA; NbExp=3; IntAct=EBI-2513774, EBI-945833;
CC O95363; Q92824-2: PCSK5; NbExp=3; IntAct=EBI-2513774, EBI-11956269;
CC O95363; Q96T49: PPP1R16B; NbExp=3; IntAct=EBI-2513774, EBI-10293968;
CC O95363; O95199: RCBTB2; NbExp=6; IntAct=EBI-2513774, EBI-742404;
CC O95363; Q9UFD9: RIMBP3; NbExp=3; IntAct=EBI-2513774, EBI-10182375;
CC O95363; O43609: SPRY1; NbExp=3; IntAct=EBI-2513774, EBI-3866665;
CC O95363; O75558: STX11; NbExp=3; IntAct=EBI-2513774, EBI-714135;
CC O95363; P08247: SYP; NbExp=3; IntAct=EBI-2513774, EBI-9071725;
CC O95363; O75478: TADA2A; NbExp=3; IntAct=EBI-2513774, EBI-742268;
CC O95363; Q96N21: TEPSIN; NbExp=3; IntAct=EBI-2513774, EBI-11139477;
CC O95363; Q12800: TFCP2; NbExp=3; IntAct=EBI-2513774, EBI-717422;
CC O95363; P07951-2: TPM2; NbExp=3; IntAct=EBI-2513774, EBI-10977815;
CC O95363; Q12933: TRAF2; NbExp=3; IntAct=EBI-2513774, EBI-355744;
CC O95363; P14373: TRIM27; NbExp=3; IntAct=EBI-2513774, EBI-719493;
CC O95363; Q9BYV2: TRIM54; NbExp=3; IntAct=EBI-2513774, EBI-2130429;
CC O95363; Q15654: TRIP6; NbExp=3; IntAct=EBI-2513774, EBI-742327;
CC O95363; O95070: YIF1A; NbExp=3; IntAct=EBI-2513774, EBI-2799703;
CC O95363; Q7Z4V0: ZNF438; NbExp=3; IntAct=EBI-2513774, EBI-11962468;
CC O95363; O60304: ZNF500; NbExp=3; IntAct=EBI-2513774, EBI-18234077;
CC O95363; Q8TF50: ZNF526; NbExp=3; IntAct=EBI-2513774, EBI-11035148;
CC O95363; Q8N720: ZNF655; NbExp=3; IntAct=EBI-2513774, EBI-625509;
CC O95363; Q9UGI0: ZRANB1; NbExp=3; IntAct=EBI-2513774, EBI-527853;
CC -!- SUBCELLULAR LOCATION: Mitochondrion matrix
CC {ECO:0000250|UniProtKB:Q6AYQ3}. Mitochondrion
CC {ECO:0000250|UniProtKB:Q6AYQ3}.
CC -!- DISEASE: Combined oxidative phosphorylation deficiency 14 (COXPD14)
CC [MIM:614946]: A severe multisystemic autosomal recessive disorder
CC characterized by neonatal onset of global developmental delay,
CC refractory seizures, and lactic acidosis. Biochemical studies show
CC deficiencies of multiple mitochondrial respiratory enzymes.
CC {ECO:0000269|PubMed:22499341, ECO:0000269|PubMed:22833457}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- DISEASE: Spastic paraplegia 77, autosomal recessive (SPG77)
CC [MIM:617046]: A form of spastic paraplegia, a neurodegenerative
CC disorder characterized by a slow, gradual, progressive weakness and
CC spasticity of the lower limbs. Rate of progression and the severity of
CC symptoms are quite variable. Initial symptoms may include difficulty
CC with balance, weakness and stiffness in the legs, muscle spasms, and
CC dragging the toes when walking. In some forms of the disorder, bladder
CC symptoms (such as incontinence) may appear, or the weakness and
CC stiffness may spread to other parts of the body.
CC {ECO:0000269|PubMed:26553276}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the class-II aminoacyl-tRNA synthetase family.
CC {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAF28998.1; Type=Frameshift; Evidence={ECO:0000305};
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DR EMBL; AF097441; AAC83802.1; -; mRNA.
DR EMBL; AK312454; BAG35361.1; -; mRNA.
DR EMBL; CR542279; CAG47075.1; -; mRNA.
DR EMBL; AK223423; BAD97143.1; -; mRNA.
DR EMBL; AL133473; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL022097; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL392184; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL121978; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL590868; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC020239; AAH20239.1; -; mRNA.
DR EMBL; BC021112; AAH21112.1; -; mRNA.
DR EMBL; AF161438; AAF28998.1; ALT_FRAME; mRNA.
DR CCDS; CCDS4494.1; -.
DR RefSeq; NP_001305801.1; NM_001318872.1.
DR RefSeq; NP_006558.1; NM_006567.4.
DR RefSeq; XP_005248869.1; XM_005248812.3.
DR RefSeq; XP_016865675.1; XM_017010186.1.
DR RefSeq; XP_016865676.1; XM_017010187.1.
DR PDB; 3CMQ; X-ray; 2.20 A; A=38-451.
DR PDB; 3HFV; X-ray; 2.60 A; A=38-451.
DR PDB; 3TEG; X-ray; 2.20 A; A=38-451.
DR PDB; 3TUP; X-ray; 3.05 A; A=38-451.
DR PDB; 5MGH; X-ray; 1.87 A; A=47-451.
DR PDB; 5MGU; X-ray; 1.89 A; A=46-451.
DR PDB; 5MGV; X-ray; 2.05 A; A=47-451.
DR PDB; 5MGW; X-ray; 1.46 A; A=46-451.
DR PDBsum; 3CMQ; -.
DR PDBsum; 3HFV; -.
DR PDBsum; 3TEG; -.
DR PDBsum; 3TUP; -.
DR PDBsum; 5MGH; -.
DR PDBsum; 5MGU; -.
DR PDBsum; 5MGV; -.
DR PDBsum; 5MGW; -.
DR AlphaFoldDB; O95363; -.
DR SMR; O95363; -.
DR BioGRID; 115909; 135.
DR IntAct; O95363; 89.
DR MINT; O95363; -.
DR STRING; 9606.ENSP00000316335; -.
DR BindingDB; O95363; -.
DR ChEMBL; CHEMBL2511; -.
DR DrugBank; DB00120; Phenylalanine.
DR iPTMnet; O95363; -.
DR PhosphoSitePlus; O95363; -.
DR BioMuta; FARS2; -.
DR EPD; O95363; -.
DR jPOST; O95363; -.
DR MassIVE; O95363; -.
DR MaxQB; O95363; -.
DR PaxDb; O95363; -.
DR PeptideAtlas; O95363; -.
DR PRIDE; O95363; -.
DR ProteomicsDB; 50824; -.
DR Antibodypedia; 2800; 126 antibodies from 24 providers.
DR DNASU; 10667; -.
DR Ensembl; ENST00000274680.9; ENSP00000274680.4; ENSG00000145982.13.
DR Ensembl; ENST00000324331.10; ENSP00000316335.5; ENSG00000145982.13.
DR GeneID; 10667; -.
DR KEGG; hsa:10667; -.
DR MANE-Select; ENST00000274680.9; ENSP00000274680.4; NM_006567.5; NP_006558.1.
DR UCSC; uc003mwr.3; human.
DR CTD; 10667; -.
DR DisGeNET; 10667; -.
DR GeneCards; FARS2; -.
DR GeneReviews; FARS2; -.
DR HGNC; HGNC:21062; FARS2.
DR HPA; ENSG00000145982; Low tissue specificity.
DR MalaCards; FARS2; -.
DR MIM; 611592; gene.
DR MIM; 614946; phenotype.
DR MIM; 617046; phenotype.
DR neXtProt; NX_O95363; -.
DR OpenTargets; ENSG00000145982; -.
DR Orphanet; 466722; Autosomal recessive spastic paraplegia type 77.
DR Orphanet; 319519; Combined oxidative phosphorylation defect type 14.
DR PharmGKB; PA134954893; -.
DR VEuPathDB; HostDB:ENSG00000145982; -.
DR eggNOG; KOG2783; Eukaryota.
DR GeneTree; ENSGT00940000158071; -.
DR HOGENOM; CLU_022696_1_0_1; -.
DR InParanoid; O95363; -.
DR OMA; SKSDTYY; -.
DR OrthoDB; 1115196at2759; -.
DR PhylomeDB; O95363; -.
DR TreeFam; TF105798; -.
DR BRENDA; 6.1.1.20; 2681.
DR PathwayCommons; O95363; -.
DR Reactome; R-HSA-379726; Mitochondrial tRNA aminoacylation.
DR SignaLink; O95363; -.
DR BioGRID-ORCS; 10667; 383 hits in 1087 CRISPR screens.
DR ChiTaRS; FARS2; human.
DR EvolutionaryTrace; O95363; -.
DR GeneWiki; FARS2; -.
DR GenomeRNAi; 10667; -.
DR Pharos; O95363; Tchem.
DR PRO; PR:O95363; -.
DR Proteomes; UP000005640; Chromosome 6.
DR RNAct; O95363; protein.
DR Bgee; ENSG00000145982; Expressed in triceps brachii and 188 other tissues.
DR ExpressionAtlas; O95363; baseline and differential.
DR Genevisible; O95363; HS.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005759; C:mitochondrial matrix; TAS:Reactome.
DR GO; GO:0005739; C:mitochondrion; ISS:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004826; F:phenylalanine-tRNA ligase activity; IDA:UniProtKB.
DR GO; GO:0000049; F:tRNA binding; IDA:UniProtKB.
DR GO; GO:0006432; P:phenylalanyl-tRNA aminoacylation; IDA:UniProtKB.
DR GO; GO:0006418; P:tRNA aminoacylation for protein translation; TAS:Reactome.
DR GO; GO:0008033; P:tRNA processing; IDA:UniProtKB.
DR Gene3D; 3.30.70.380; -; 1.
DR Gene3D; 3.30.930.10; -; 1.
DR InterPro; IPR006195; aa-tRNA-synth_II.
DR InterPro; IPR045864; aa-tRNA-synth_II/BPL/LPL.
DR InterPro; IPR005121; Fdx_antiC-bd.
DR InterPro; IPR036690; Fdx_antiC-bd_sf.
DR InterPro; IPR004530; Phe-tRNA-synth_IIc_mito.
DR InterPro; IPR002319; Phenylalanyl-tRNA_Synthase.
DR PANTHER; PTHR11538:SF41; PTHR11538:SF41; 1.
DR Pfam; PF03147; FDX-ACB; 1.
DR Pfam; PF01409; tRNA-synt_2d; 2.
DR SMART; SM00896; FDX-ACB; 1.
DR SUPFAM; SSF54991; SSF54991; 1.
DR SUPFAM; SSF55681; SSF55681; 1.
DR TIGRFAMs; TIGR00469; pheS_mito; 1.
DR PROSITE; PS50862; AA_TRNA_LIGASE_II; 1.
DR PROSITE; PS51447; FDX_ACB; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Aminoacyl-tRNA synthetase; ATP-binding;
KW Disease variant; Hereditary spastic paraplegia; Ligase; Mitochondrion;
KW Neurodegeneration; Nucleotide-binding; Primary mitochondrial disease;
KW Protein biosynthesis; Reference proteome; Transit peptide.
FT TRANSIT 1..?
FT /note="Mitochondrion"
FT /evidence="ECO:0000255"
FT CHAIN ?..451
FT /note="Phenylalanine--tRNA ligase, mitochondrial"
FT /id="PRO_0000035813"
FT DOMAIN 358..450
FT /note="FDX-ACB"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00778"
FT BINDING 157..160
FT /ligand="substrate"
FT BINDING 179
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:18611382,
FT ECO:0000269|PubMed:19549855"
FT BINDING 186..188
FT /ligand="substrate"
FT BINDING 193..195
FT /ligand="substrate"
FT BINDING 287
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:18611382,
FT ECO:0000269|PubMed:19549855"
FT BINDING 312
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:18611382,
FT ECO:0000269|PubMed:19549855"
FT MOD_RES 202
FT /note="N6-acetyllysine"
FT /evidence="ECO:0007744|PubMed:19608861"
FT VARIANT 57
FT /note="S -> C (in dbSNP:rs34382405)"
FT /id="VAR_052642"
FT VARIANT 142
FT /note="D -> Y (in SPG77; resulted in severely impaired
FT phenylalanine-tRNA ligase activity; dbSNP:rs145555213)"
FT /evidence="ECO:0000269|PubMed:26553276"
FT /id="VAR_077044"
FT VARIANT 144
FT /note="Y -> C (in COXPD14; results in decreased affinity
FT for tRNA causing a decrease in the catalytic efficiency for
FT tRNA charging; does not affect ATP or Phe binding;
FT dbSNP:rs397514610)"
FT /evidence="ECO:0000269|PubMed:22499341,
FT ECO:0000269|PubMed:22833457"
FT /id="VAR_069487"
FT VARIANT 280
FT /note="N -> S (in dbSNP:rs11243011)"
FT /evidence="ECO:0000269|PubMed:14702039, ECO:0000269|Ref.3,
FT ECO:0000269|Ref.7"
FT /id="VAR_052643"
FT VARIANT 329
FT /note="I -> T (in COXPD14; results in a 4-fold decrease in
FT the catalytic efficiency of amino acid activation mainly
FT due to a decreased affinity for ATP; does not affect Phe
FT binding; affects the stability of the enzyme, leading to a
FT significant decrease in overall charging capacity;
FT dbSNP:rs397514611)"
FT /evidence="ECO:0000269|PubMed:22833457"
FT /id="VAR_069488"
FT VARIANT 391
FT /note="D -> V (in COXPD14; results in a decrease in
FT affinity for Phe causing a decrease in aminoacylation
FT activity; affects the stability of the enzyme, leading to a
FT significant decrease in overall charging capacity;
FT dbSNP:rs397514612)"
FT /evidence="ECO:0000269|PubMed:22833457"
FT /id="VAR_069489"
FT CONFLICT 158
FT /note="A -> T (in Ref. 4; BAD97143)"
FT /evidence="ECO:0000305"
FT CONFLICT 361
FT /note="P -> T (in Ref. 7; AAF28998)"
FT /evidence="ECO:0000305"
FT STRAND 49..53
FT /evidence="ECO:0007829|PDB:5MGW"
FT STRAND 56..59
FT /evidence="ECO:0007829|PDB:5MGW"
FT HELIX 68..71
FT /evidence="ECO:0007829|PDB:5MGW"
FT TURN 72..75
FT /evidence="ECO:0007829|PDB:5MGW"
FT HELIX 78..80
FT /evidence="ECO:0007829|PDB:5MGW"
FT STRAND 81..84
FT /evidence="ECO:0007829|PDB:3TUP"
FT HELIX 85..99
FT /evidence="ECO:0007829|PDB:5MGW"
FT STRAND 104..106
FT /evidence="ECO:0007829|PDB:5MGH"
FT STRAND 111..113
FT /evidence="ECO:0007829|PDB:5MGW"
FT STRAND 118..121
FT /evidence="ECO:0007829|PDB:5MGW"
FT HELIX 122..125
FT /evidence="ECO:0007829|PDB:5MGW"
FT HELIX 127..129
FT /evidence="ECO:0007829|PDB:5MGW"
FT HELIX 136..138
FT /evidence="ECO:0007829|PDB:5MGW"
FT TURN 140..142
FT /evidence="ECO:0007829|PDB:5MGW"
FT STRAND 145..152
FT /evidence="ECO:0007829|PDB:5MGW"
FT HELIX 156..159
FT /evidence="ECO:0007829|PDB:5MGW"
FT HELIX 160..165
FT /evidence="ECO:0007829|PDB:5MGW"
FT STRAND 169..178
FT /evidence="ECO:0007829|PDB:5MGW"
FT STRAND 184..186
FT /evidence="ECO:0007829|PDB:3TUP"
FT STRAND 189..200
FT /evidence="ECO:0007829|PDB:5MGW"
FT HELIX 202..205
FT /evidence="ECO:0007829|PDB:5MGW"
FT TURN 206..208
FT /evidence="ECO:0007829|PDB:5MGW"
FT HELIX 212..214
FT /evidence="ECO:0007829|PDB:5MGH"
FT HELIX 233..255
FT /evidence="ECO:0007829|PDB:5MGW"
FT HELIX 256..258
FT /evidence="ECO:0007829|PDB:3HFV"
FT STRAND 261..268
FT /evidence="ECO:0007829|PDB:5MGW"
FT STRAND 271..281
FT /evidence="ECO:0007829|PDB:5MGW"
FT STRAND 284..294
FT /evidence="ECO:0007829|PDB:5MGW"
FT HELIX 296..301
FT /evidence="ECO:0007829|PDB:5MGW"
FT STRAND 308..315
FT /evidence="ECO:0007829|PDB:5MGW"
FT HELIX 316..324
FT /evidence="ECO:0007829|PDB:5MGW"
FT HELIX 329..333
FT /evidence="ECO:0007829|PDB:5MGW"
FT HELIX 337..340
FT /evidence="ECO:0007829|PDB:5MGW"
FT HELIX 341..343
FT /evidence="ECO:0007829|PDB:5MGW"
FT STRAND 363..370
FT /evidence="ECO:0007829|PDB:5MGW"
FT HELIX 378..389
FT /evidence="ECO:0007829|PDB:5MGW"
FT HELIX 390..392
FT /evidence="ECO:0007829|PDB:5MGW"
FT STRAND 393..403
FT /evidence="ECO:0007829|PDB:5MGW"
FT TURN 405..407
FT /evidence="ECO:0007829|PDB:5MGW"
FT STRAND 410..418
FT /evidence="ECO:0007829|PDB:5MGW"
FT STRAND 421..423
FT /evidence="ECO:0007829|PDB:5MGW"
FT HELIX 427..445
FT /evidence="ECO:0007829|PDB:5MGW"
FT STRAND 448..451
FT /evidence="ECO:0007829|PDB:3HFV"
SQ SEQUENCE 451 AA; 52357 MW; 1E5CC647A4A7193B CRC64;
MVGSALRRGA HAYVYLVSKA SHISRGHQHQ AWGSRPPAAE CATQRAPGSV VELLGKSYPQ
DDHSNLTRKV LTRVGRNLHN QQHHPLWLIK ERVKEHFYKQ YVGRFGTPLF SVYDNLSPVV
TTWQNFDSLL IPADHPSRKK GDNYYLNRTH MLRAHTSAHQ WDLLHAGLDA FLVVGDVYRR
DQIDSQHYPI FHQLEAVRLF SKHELFAGIK DGESLQLFEQ SSRSAHKQET HTMEAVKLVE
FDLKQTLTRL MAHLFGDELE IRWVDCYFPF THPSFEMEIN FHGEWLEVLG CGVMEQQLVN
SAGAQDRIGW AFGLGLERLA MILYDIPDIR LFWCEDERFL KQFCVSNINQ KVKFQPLSKY
PAVINDISFW LPSENYAEND FYDLVRTIGG DLVEKVDLID KFVHPKTHKT SHCYRITYRH
MERTLSQREV RHIHQALQEA AVQLLGVEGR F
