P12081 (SYHC_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Histidine--tRNA ligase, cytoplasmic
EC=6.1.1.21

Alternative name(s):
Histidyl-tRNA synthetase
Short name=HisRS

Gene names

Name:	HARS
Synonyms:	HRS

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	509 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Catalytic activity	ATP + L-histidine + tRNA(His) = AMP + diphosphate + L-histidyl-tRNA(His).
Subcellular location	Cytoplasm.
Tissue specificity	Brain, heart, liver and kidney.
Involvement in disease	Usher syndrome 3B (USH3B) [MIM:614504]: A syndrome characterized by progressive vision and hearing loss during early childhood. Some patients have the so-called 'Charles Bonnet syndrome,' involving decreased visual acuity and vivid visual hallucinations. USH is a genetically heterogeneous condition characterized by the association of retinitis pigmentosa with sensorineural deafness. Age at onset and differences in auditory and vestibular function distinguish Usher syndrome type 1 (USH1), Usher syndrome type 2 (USH2) and Usher syndrome type 3 (USH3). USH3 is characterized by postlingual, progressive hearing loss, variable vestibular dysfunction, and onset of retinitis pigmentosa symptoms, including nyctalopia, constriction of the visual fields, and loss of central visual acuity, usually by the second decade of life. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.11 HARS mutations may be involved in peripheral neuropathy, a disease mainly characterized by distal motor and sensory dysfunction. Inherited peripheral neuropathies are clinically and genetically heterogeneous with variable age of onset and reduced penetrance associated with specific loci. HARS mutations may directly predispose patients to peripheral neuropathy or may modify a peripheral neuropathy phenotype by contributing to the genetic and environmental load in a given patient (Ref.9).
Sequence similarities	Belongs to the class-II aminoacyl-tRNA synthetase family. Contains 1 WHEP-TRS domain.
Sequence caution	The sequence CAA28956.1 differs from that shown. Reason: Frameshift at several positions.

Ontologies

Keywords
Biological process	Protein biosynthesis
Cellular component	Cytoplasm
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Deafness Disease mutation Neuropathy Retinitis pigmentosa Usher syndrome
Ligand	ATP-binding Nucleotide-binding
Molecular function	Aminoacyl-tRNA synthetase Ligase
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	histidyl-tRNA aminoacylation Inferred from electronic annotation. Source: InterPro tRNA aminoacylation for protein translation Traceable author statement. Source: Reactome
Cellular_component	cytosol Traceable author statement. Source: Reactome
Molecular_function	ATP binding Non-traceable author statement. Source: UniProtKB histidine-tRNA ligase activity Non-traceable author statement Ref.1Ref.7. Source: UniProtKB
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: P12081-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: P12081-2)

The sequence of this isoform differs from the canonical sequence as follows:
     60-99: Missing.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 509

509

Histidine--tRNA ligase, cytoplasmic

PRO_0000136332

Regions

Domain

3 – 59

57

WHEP-TRS

Natural variations

Alternative sequence

60 – 99

40

Missing in isoform 2.

VSP_045118

Natural variant

5

1

A → E. Ref.9
Corresponds to variant rs78741041 [ dbSNP | Ensembl ].

VAR_069021

Natural variant

137

1

R → Q Found in a patient with peripheral neuropathy; unknown pathological significance; results in loss of function; has a neurotoxic effect in an animal model. Ref.9
Corresponds to variant rs191391414 [ dbSNP | Ensembl ].

VAR_069022

Natural variant

205

1

G → D. Ref.9
Corresponds to variant rs147288996 [ dbSNP | Ensembl ].

VAR_069023

Natural variant

238

1

V → A Found in a patient with peripheral neuropathy; unknown pathological role. Ref.9

VAR_069024

Natural variant

376

1

K → R. Ref.9
Corresponds to variant rs139447495 [ dbSNP | Ensembl ].

VAR_069025

Natural variant

399

1

A → V.
Corresponds to variant rs34732372 [ dbSNP | Ensembl ].

VAR_061908

Natural variant

454

1

Y → S in USH3B. Ref.11

VAR_067918

Natural variant

505

1

P → S Found in a patient with peripheral neuropathy; unknown pathological role. Ref.9

VAR_069026

Experimental info

Sequence conflict

6

1

A → P in CAA28956. Ref.2

Sequence conflict

165

1

R → G in CAA28956. Ref.2

Sequence conflict

181

1

N → Q in CAA28956. Ref.2

Sequence conflict

186

1

I → N in CAA28956. Ref.2

Sequence conflict

191

1

C → S in CAA28956. Ref.2

Sequence conflict

206

1

D → N in CAA28956. Ref.2

Sequence conflict

223

1

I → V in CAA28956. Ref.2

Sequence conflict

227

1

S → P in CAA28956. Ref.2

Sequence conflict

284

1

L → V in CAA28956. Ref.2

Sequence conflict

347

1

A → E in CAA28956. Ref.2

Sequence conflict

373 – 374

2

KG → QR in CAA28956. Ref.2

Sequence conflict

493

1

D → E in CAA28956. Ref.2

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

509

Helix Strand Turn

Details...

Helix

1 – 23

23

Helix

28 – 45

18

Helix

67 – 86

20

Beta strand

96 – 99

4

Helix

100 – 103

4

Beta strand

125 – 127

3

Helix

132 – 141

10

Beta strand

147 – 156

10

Beta strand

169 – 180

12

Helix

186 – 202

17

Beta strand

207 – 213

7

Helix

214 – 224

11

Helix

228 – 238

11

Helix

239 – 242

4

Helix

246 – 255

10

Helix

261 – 271

11

Beta strand

274 – 276

3

Helix

277 – 283

7

Helix

287 – 290

4

Helix

293 – 311

19

Helix

315 – 317

3

Beta strand

318 – 321

4

Turn

328 – 330

3

Beta strand

332 – 342

11

Beta strand

352 – 362

11

Helix

367 – 369

3

Beta strand

371 – 373

3

Beta strand

379 – 384

6

Helix

386 – 398

13

Turn

399 – 401

3

Beta strand

411 – 414

4

Beta strand

416 – 419

4

Helix

421 – 433

13

Beta strand

438 – 440

3

Beta strand

442 – 445

4

Helix

448 – 458

11

Beta strand

462 – 465

4

Helix

468 – 473

6

Beta strand

475 – 480

6

Turn

481 – 483

3

Beta strand

486 – 490

5

Helix

491 – 493

3

Helix

494 – 502

9

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified May 1, 1992. Version 2. Checksum: 65D8BB71CE79B1FF	FASTA	509	57,411
	10 20 30 40 50 60 MAERAALEEL VKLQGERVRG LKQQKASAEL IEEEVAKLLK LKAQLGPDES KQKFVLKTPK 70 80 90 100 110 120 GTRDYSPRQM AVREKVFDVI IRCFKRHGAE VIDTPVFELK ETLMGKYGED SKLIYDLKDQ 130 140 150 160 170 180 GGELLSLRYD LTVPFARYLA MNKLTNIKRY HIAKVYRRDN PAMTRGRYRE FYQCDFDIAG 190 200 210 220 230 240 NFDPMIPDAE CLKIMCEILS SLQIGDFLVK VNDRRILDGM FAICGVSDSK FRTICSSVDK 250 260 270 280 290 300 LDKVSWEEVK NEMVGEKGLA PEVADRIGDY VQQHGGVSLV EQLLQDPKLS QNKQALEGLG 310 320 330 340 350 360 DLKLLFEYLT LFGIDDKISF DLSLARGLDY YTGVIYEAVL LQTPAQAGEE PLGVGSVAAG 370 380 390 400 410 420 GRYDGLVGMF DPKGRKVPCV GLSIGVERIF SIVEQRLEAL EEKIRTTETQ VLVASAQKKL 430 440 450 460 470 480 LEERLKLVSE LWDAGIKAEL LYKKNPKLLN QLQYCEEAGI PLVAIIGEQE LKDGVIKLRS 490 500 VTSREEVDVR REDLVEEIKR RTGQPLCIC
	Isoform 2 [UniParc]. Checksum: B02783AB9FED1E1D	FASTA	469	52,720
	10 20 30 40 50 60 MAERAALEEL VKLQGERVRG LKQQKASAEL IEEEVAKLLK LKAQLGPDES KQKFVLKTPK 70 80 90 100 110 120 ETLMGKYGED SKLIYDLKDQ GGELLSLRYD LTVPFARYLA MNKLTNIKRY HIAKVYRRDN 130 140 150 160 170 180 PAMTRGRYRE FYQCDFDIAG NFDPMIPDAE CLKIMCEILS SLQIGDFLVK VNDRRILDGM 190 200 210 220 230 240 FAICGVSDSK FRTICSSVDK LDKVSWEEVK NEMVGEKGLA PEVADRIGDY VQQHGGVSLV 250 260 270 280 290 300 EQLLQDPKLS QNKQALEGLG DLKLLFEYLT LFGIDDKISF DLSLARGLDY YTGVIYEAVL 310 320 330 340 350 360 LQTPAQAGEE PLGVGSVAAG GRYDGLVGMF DPKGRKVPCV GLSIGVERIF SIVEQRLEAL 370 380 390 400 410 420 EEKIRTTETQ VLVASAQKKL LEERLKLVSE LWDAGIKAEL LYKKNPKLLN QLQYCEEAGI 430 440 450 460 PLVAIIGEQE LKDGVIKLRS VTSREEVDVR REDLVEEIKR RTGQPLCIC

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Human histidyl-tRNA synthetase: recognition of amino acid signature regions in class 2a aminoacyl-tRNA synthetases." Raben N., Borriello F., Amin J., Horwitz R., Fraser D., Plotz P. Nucleic Acids Res. 20:1075-1081(1992) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[2]	"Isolation, structure and expression of mammalian genes for histidyl-tRNA synthetase." Tsui F.W.L., Siminovitch L. Nucleic Acids Res. 15:3349-3367(1987) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[3]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). Tissue: Testis.
[4]	"The DNA sequence and comparative analysis of human chromosome 5." Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S., Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M., She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S. , Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M., Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T., Gomez M., Gonzales E., Goodstein D., Grigoriev I., Groza M., Hammon N., Hawkins T., Haydu L., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Lopez F., Lou Y., Martinez D., Medina C., Morgan J., Nandkeshwar R., Noonan J.P., Pitluck S., Pollard M., Predki P., Priest J., Ramirez L., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., Thayer N., Tice H., Tsai M., Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., Dickson M., Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., Rokhsar D.S., Richardson P., Lucas S.M., Myers R.M., Rubin E.M. Nature 431:268-274(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). Tissue: Lung and Uterus.
[6]	"Transcriptional analyses of the gene region that encodes human histidyl-tRNA synthetase: identification of a novel bidirectional regulatory element." Tsui H.W., Mok S., de Souza L., Martin A., Tsui F.W.L. Gene 131:201-208(1993) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-30.
[7]	"A novel gene oriented in a head-to-head configuration with the human histidyl-tRNA synthetase (HRS) gene encodes an mRNA that predicts a polypeptide homologous to HRS." O'Hanlon T.P., Raben N., Miller F.W. Biochem. Biophys. Res. Commun. 210:556-566(1995) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-30.
[8]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[9]	"A loss-of-function variant in the human histidyl-tRNA synthetase (HARS) gene is neurotoxic in vivo." NISC comparative sequencing program Vester A., Velez-Ruiz G., McLaughlin H.M., Lupski J.R., Talbot K., Vance J.M., Zuchner S., Roda R.H., Fischbeck K.H., Biesecker L.G., Nicholson G., Beg A.A., Antonellis A. Hum. Mutat. 34:191-199(2013) [PubMed] [Europe PMC] [Abstract] Cited for: POSSIBLE INVOLVEMENT IN PERIPHERAL NEUROPATHY, VARIANTS GLU-5; GLN-137; ASP-205; ALA-238; ARG-376 AND SER-505, CHARACTERIZATION OF VARIANT GLN-137.
[10]	"Solution structures of the WHEP-TRS domain of human histidyl-tRNA synthetase." RIKEN structural genomics initiative (RSGI) Submitted (NOV-2005) to the PDB data bank Cited for: STRUCTURE BY NMR OF 1-60.
[11]	"Genetic mapping and exome sequencing identify variants associated with five novel diseases." Puffenberger E.G., Jinks R.N., Sougnez C., Cibulskis K., Willert R.A., Achilly N.P., Cassidy R.P., Fiorentini C.J., Heiken K.F., Lawrence J.J., Mahoney M.H., Miller C.J., Nair D.T., Politi K.A., Worcester K.N., Setton R.A., Dipiazza R., Sherman E.A. , Eastman J.T., Francklyn C., Robey-Bond S., Rider N.L., Gabriel S., Morton D.H., Strauss K.A. PLoS ONE 7:E28936-E28936(2012) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT USH3B SER-454.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

Z11518 mRNA. Translation: CAA77607.1.
X05345 mRNA. Translation: CAA28956.1. Frameshift.
AK302295 mRNA. Translation: BAG63635.1.
AC116353 Genomic DNA. No translation available.
BC011807 mRNA. Translation: AAH11807.1.
BC080514 mRNA. Translation: AAH80514.1.
M96646 Genomic DNA. Translation: AAA58668.1.
U18936 Genomic DNA. Translation: AAA73973.1.

IPI

IPI00021808.

PIR

SYHUHT. I37559.

RefSeq

NP_001244969.1. NM_001258040.1.
NP_002100.2. NM_002109.4.

UniGene

Hs.528050.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1X59	NMR	-	A	1-60	[»]
4G84	X-ray	2.40	A/B	54-506	[»]
4G85	X-ray	3.11	A/B	1-506	[»]

ProteinModelPortal

P12081.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-37596N.

IntAct

P12081. 1 interaction.

STRING

9606.ENSP00000304668.

PTM databases

PhosphoSite

P12081.

Polymorphism databases

DMDM

135123.

Proteomic databases

PaxDb

P12081.

PeptideAtlas

P12081.

PRIDE

P12081.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000438307; ENSP00000411511; ENSG00000170445.
ENST00000504156; ENSP00000425634; ENSG00000170445.

GeneID

3035.

KEGG

hsa:3035.

UCSC

uc003lgu.3. human.

Organism-specific databases

CTD

3035.

GeneCards

GC05M140034.

HGNC

HGNC:4816. HARS.

HPA

HPA036539.

MIM

142810. gene.
614504. phenotype.

neXtProt

NX_P12081.

Orphanet

231183. Usher syndrome type 3.

PharmGKB

PA29191.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0124.

HOGENOM

HOG000018075.

HOVERGEN

HBG002731.

InParanoid

P12081.

KO

K01892.

OMA

RGERAQK.

PhylomeDB

P12081.

Enzyme and pathway databases

BRENDA

6.1.1.21. 2681.

Reactome

REACT_71. Gene Expression.

Gene expression databases

ArrayExpress

P12081.

Bgee

P12081.

CleanEx

HS_HARS.

Genevestigator

P12081.

GermOnline

ENSG00000170445. Homo sapiens.

Family and domain databases

Gene3D

1.10.287.10. 1 hit.
3.40.50.800. 1 hit.

InterPro

IPR002314. aa-tRNA-synt_IIb_cons-dom.
IPR006195. aa-tRNA-synth_II.
IPR004154. Anticodon-bd.
IPR015807. His-tRNA-ligase.
IPR004516. HisRS/HisZ.
IPR009068. S15_NS1_RNA-bd.
IPR000738. WHEP-TRS.
[Graphical view]

PANTHER

PTHR11476. PTHR11476. 1 hit.

Pfam

PF03129. HGTP_anticodon. 1 hit.
PF00587. tRNA-synt_2b. 1 hit.
PF00458. WHEP-TRS. 1 hit.
[Graphical view]

PIRSF

PIRSF001549. His-tRNA_synth. 1 hit.

SMART

SM00991. WHEP-TRS. 1 hit.
[Graphical view]

SUPFAM

SSF52954. Anticodon_bd. 1 hit.
SSF47060. S15/NS1_bind. 1 hit.

TIGRFAMs

TIGR00442. hisS. 1 hit.

PROSITE

PS50862. AA_TRNA_LIGASE_II. 1 hit.
PS00762. WHEP_TRS_1. 1 hit.
PS51185. WHEP_TRS_2. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

P12081.

ChEMBL

CHEMBL4002.

ChiTaRS

HARS. human.

DrugBank

DB00117. L-Histidine.

EvolutionaryTrace

P12081.

GenomeRNAi

3035.

NextBio

12014.

SOURCE

Search...

Entry information

Entry name

SYHC_HUMAN

Accession

Primary (citable) accession number: P12081
Secondary accession number(s): B4DY73

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1989
Last sequence update:	May 1, 1992
Last modified:	May 1, 2013
This is version 142 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.