P19429 (TNNI3_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Troponin I, cardiac muscle

Alternative name(s):
Cardiac troponin I

Gene names

Name:	TNNI3
Synonyms:	TNNC1

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	210 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Troponin I is the inhibitory subunit of troponin, the thin filament regulatory complex which confers calcium-sensitivity to striated muscle actomyosin ATPase activity.
Subunit structure	Binds to actin and tropomyosin. Interacts with TRIM63. Interacts with STK4/MST1. Ref.9 Ref.10
Post-translational modification	Phosphorylated at Ser-42 and Ser-44 by PRKCE; phosphorylation increases myocardium contractile dysfunction By similarity. Phosphorylated at Ser-23 and Ser-24 by PRKD1; phosphorylation reduces myofilament calcium sensitivity. Phosphorylated preferentially at Thr-31. Phosphorylation by STK4/MST1 alters its binding affinity to TNNC1 (cardiac Tn-C) and TNNT2 (cardiac Tn-T). Ref.5 Ref.6 Ref.7 Ref.8 Ref.10 Ref.11
Involvement in disease	Cardiomyopathy, familial hypertrophic 7 (CMH7) [MIM:613690]: A hereditary heart disorder characterized by ventricular hypertrophy, which is usually asymmetric and often involves the interventricular septum. The symptoms include dyspnea, syncope, collapse, palpitations, and chest pain. They can be readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.14 Ref.15 Ref.17 Ref.19 Ref.21 Cardiomyopathy, familial restrictive 1 (RCM1) [MIM:115210]: A heart disorder characterized by impaired filling of the ventricles with reduced diastolic volume, in the presence of normal or near normal wall thickness and systolic function. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.16 Cardiomyopathy, dilated 2A (CMD2A) [MIM:611880]: A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.20 Cardiomyopathy, dilated 1FF (CMD1FF) [MIM:613286]: A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.22 Ref.23
Sequence similarities	Belongs to the troponin I family.

Ontologies

Keywords
Disease	Cardiomyopathy Disease mutation
Ligand	Actin-binding Calcium Metal-binding
Molecular function	Muscle protein
PTM	Acetylation Phosphoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	cardiac muscle contraction Inferred from mutant phenotype PubMed 11735257. Source: UniProtKB cellular calcium ion homeostasis Inferred from sequence or structural similarity. Source: UniProtKB muscle filament sliding Traceable author statement. Source: Reactome negative regulation of ATPase activity Inferred from direct assay PubMed 11735257PubMed 7957210. Source: UniProtKB regulation of smooth muscle contraction Inferred from electronic annotation. Source: Compara regulation of systemic arterial blood pressure by ischemic conditions Inferred from sequence or structural similarity. Source: UniProtKB vasculogenesis Inferred from sequence or structural similarity. Source: UniProtKB ventricular cardiac muscle tissue morphogenesis Inferred from mutant phenotype PubMed 16754800. Source: BHF-UCL
Cellular_component	cytosol Traceable author statement. Source: Reactome troponin complex Inferred from direct assay PubMed 10806205PubMed 10850966PubMed 12093807PubMed 7957210. Source: UniProtKB
Molecular_function	actin binding Inferred from direct assay PubMed 10806205. Source: UniProtKB calcium channel inhibitor activity Inferred from physical interaction PubMed 12809519. Source: UniProtKB metal ion binding Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
TNNI3K	Q59H18	2	EBI-704146,EBI-704142

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Initiator methionine

1

1

Removed

Chain

2 – 210

209

Troponin I, cardiac muscle

PRO_0000186151

Regions

Calcium binding

137 – 148

12

By similarity

Region

32 – 79

48

Involved in binding TNC

Region

129 – 149

21

Involved in binding TNC and actin

Sites

Site

80

1

Involved in TNI-TNT interactions

Site

97

1

Involved in TNI-TNT interactions

Amino acid modifications

Modified residue

2

1

N-acetylalanine Ref.5

Modified residue

5

1

Phosphoserine Ref.11

Modified residue

6

1

Phosphoserine Ref.11

Modified residue

23

1

Phosphoserine; by PKA and PKD/PRKD1 Ref.5 Ref.6 Ref.8 Ref.11

Modified residue

24

1

Phosphoserine; by PKA and PKD/PRKD1 Ref.5 Ref.6 Ref.8 Ref.11

Modified residue

26

1

Phosphotyrosine Ref.11

Modified residue

31

1

Phosphothreonine; by STK4/MST1 Ref.10

Modified residue

42

1

Phosphoserine; by PKC/PRKCE By similarity

Modified residue

44

1

Phosphoserine; by PKC/PRKCE By similarity

Modified residue

51

1

Phosphothreonine; by STK4/MST1 Ref.10 Ref.11

Modified residue

77

1

Phosphoserine Ref.11

Modified residue

78

1

Phosphothreonine Ref.11

Modified residue

129

1

Phosphothreonine; by STK4/MST1 Ref.10

Modified residue

143

1

Phosphothreonine; by STK4/MST1 Ref.10 Ref.11

Modified residue

150

1

Phosphoserine; by PAK3 Ref.7

Modified residue

166

1

Phosphoserine Ref.11

Modified residue

181

1

Phosphothreonine Ref.11

Modified residue

199

1

Phosphoserine Ref.11

Natural variations

Natural variant

2

1

A → V in CMD2A. Ref.20

VAR_043989

Natural variant

36

1

K → Q in CMD1FF. Ref.22

VAR_063548

Natural variant

79

1

R → C.
Corresponds to variant rs3729712 [ dbSNP | Ensembl ].

VAR_029453

Natural variant

82

1

P → S in CMH7. Ref.15

VAR_016078

Natural variant

116

1

A → G in CMD1FF. Ref.23

VAR_067264

Natural variant

141

1

R → Q in CMH7. Ref.17

VAR_019872

Natural variant

144

1

L → Q in RCM1. Ref.16

VAR_016079

Natural variant

145

1

R → G in CMH7. Ref.14

VAR_007603

Natural variant

145

1

R → W in RCM1. Ref.16
Corresponds to variant rs28934871 [ dbSNP | Ensembl ].

VAR_016080

Natural variant

157

1

A → V in CMH7. Ref.17

VAR_019873

Natural variant

162

1

R → P in CMH7. Ref.17 Ref.21

VAR_019874

Natural variant

162

1

R → Q in CMH7. Ref.21

VAR_042745

Natural variant

166

1

S → F in CMH7. Ref.19

VAR_029454

Natural variant

171

1

A → T in RCM1. Ref.16

VAR_016081

Natural variant

177

1

Missing in CMH7. Ref.17

VAR_019875

Natural variant

178

1

K → E in RCM1. Ref.16
Corresponds to variant rs28934870 [ dbSNP | Ensembl ].

VAR_016082

Natural variant

185

1

N → K in CMD1FF. Ref.22

VAR_063549

Natural variant

186

1

R → Q in CMH7. Ref.17

VAR_019876

Natural variant

190

1

D → H in CMH7 and RCM1. Ref.16

VAR_016083

Natural variant

192

1

R → H in RCM1. Ref.16

VAR_016084

Natural variant

196

1

D → N in CMH7. Ref.15 Ref.17

VAR_016085

Natural variant

204

1

R → H in CMH7. Ref.21

VAR_042746

Natural variant

206

1

K → Q in CMH7. Ref.14

VAR_007604

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

210

Helix Strand Turn

Details...

Helix

43 – 79

37

Helix

85 – 87

3

Helix

90 – 135

46

Helix

151 – 158

8

Turn

159 – 162

4

Sequences

	Sequence		Length	Mass (Da)
	P19429 [UniParc]. Last modified January 23, 2007. Version 3. Checksum: 20A804F8C24AE1B0	FASTA	210	24,008
	10 20 30 40 50 60 MADGSSDAAR EPRPAPAPIR RRSSNYRAYA TEPHAKKKSK ISASRKLQLK TLLLQIAKQE 70 80 90 100 110 120 LEREAEERRG EKGRALSTRC QPLELAGLGF AELQDLCRQL HARVDKVDEE RYDIEAKVTK 130 140 150 160 170 180 NITEIADLTQ KIFDLRGKFK RPTLRRVRIS ADAMMQALLG ARAKESLDLR AHLKQVKKED 190 200 210 TEKENREVGD WRKNIDALSG MEGRKKKFES

References

[1]	"Molecular cloning of human cardiac troponin I using polymerase chain reaction." Vallins W.J., Brand N.J., Dabhade N., Butler-Browne G., Yacoub M.H., Barton P.J.R. FEBS Lett. 270:57-61(1990) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Heart muscle.
[2]	"Cloning and expression in Escherichia coli of the cDNA encoding human cardiac troponin I." Armour K.L., Harris W.J., Tempest P.R. Gene 131:287-292(1993) [PubMed] [Europe PMC] [Abstract] Cited for: SEQUENCE REVISION [MRNA] TO 85, NUCLEOTIDE SEQUENCE [MRNA].
[3]	"Troponin I isoform expression in human heart." Hunkeler N.M., Kullman J., Murphy A.M. Circ. Res. 69:1409-1414(1991) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[4]	"Isolation and characterization of the human cardiac troponin I gene (TNNI3)." Bhavsar P.K., Brand N.J., Yacoub M.H., Barton P.J.R. Genomics 35:11-23(1996) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[5]	"A common motif of two adjacent phosphoserines in bovine, rabbit and human cardiac troponin I." Mittmann K., Jaquet K., Heilmeyer L.M.G. Jr. FEBS Lett. 273:41-45(1990) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 11-36, ACETYLATION AT ALA-2, PHOSPHORYLATION AT SER-23 AND SER-24.
[6]	"The ordered phosphorylation of cardiac troponin I by the cAMP-dependent protein kinase -- structural consequences and functional implications." Keane N.E., Quirk P.G., Gao Y., Patchell V.B., Perry S.V., Levine B.A. Eur. J. Biochem. 248:329-337(1997) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT SER-23 AND SER-24.
[7]	"p21-activated kinase increases the calcium sensitivity of rat triton-skinned cardiac muscle fiber bundles via a mechanism potentially involving novel phosphorylation of troponin I." Buscemi N., Foster D.B., Neverova I., Van Eyk J.E. Circ. Res. 91:509-516(2002) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT SER-150 BY PAK3.
[8]	"Protein kinase D is a novel mediator of cardiac troponin I phosphorylation and regulates myofilament function." Haworth R.S., Cuello F., Herron T.J., Franzen G., Kentish J.C., Gautel M., Avkiran M. Circ. Res. 95:1091-1099(2004) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT SER-23 AND SER-24.
[9]	"Muscle-specific RING finger 1 is a bona fide ubiquitin ligase that degrades cardiac troponin I." Kedar V., McDonough H., Arya R., Li H.-H., Rockman H.A., Patterson C. Proc. Natl. Acad. Sci. U.S.A. 101:18135-18140(2004) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH TRIM63.
[10]	"Phosphorylation of cardiac troponin I by mammalian sterile 20-like kinase 1." You B., Yan G., Zhang Z., Yan L., Li J., Ge Q., Jin J.P., Sun J. Biochem. J. 418:93-101(2009) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH STK4/MST1, PHOSPHORYLATION AT THR-31; THR-51; THR-129 AND THR-143.
[11]	"Multiple reaction monitoring to identify site-specific troponin I phosphorylated residues in the failing human heart." Zhang P., Kirk J.A., Ji W., dos Remedios C.G., Kass D.A., Van Eyk J.E., Murphy A.M. Circulation 126:1828-1837(2012) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT SER-5; SER-6; SER-23; SER-24; TYR-26; SER-42; SER-44; THR-51; SER-77; THR-78; THR-143; SER-166; THR-181 AND SER-199.
[12]	"Binding of cardiac troponin-I147-163 induces a structural opening in human cardiac troponin-C." Li M.X., Spyracopoulos L., Sykes B.D. Biochemistry 38:8289-8298(1999) [PubMed] [Europe PMC] [Abstract] Cited for: STRUCTURE BY NMR OF 148-164.
[13]	"Structure of the regulatory N-domain of human cardiac troponin C in complex with human cardiac troponin I147-163 and bepridil." Wang X., Li M.X., Sykes B.D. J. Biol. Chem. 277:31124-31133(2002) [PubMed] [Europe PMC] [Abstract] Cited for: STRUCTURE BY NMR OF 149-165 IN COMPLEX WITH CARDIAC TROPONIN C.
[14]	"Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy." Kimura A., Harada H., Park J.-E., Nishi H., Satoh M., Takahashi M., Hiroi S., Sasaoka T., Ohbuchi N., Nakamura T., Koyanagi T., Hwang T.-H., Choo J., Chung K.-S., Hasegawa A., Nagai R., Okazaki O., Nakamura H. , Matsuzaki M., Sakamoto T., Toshima H., Koga Y., Imaizumi T., Sasazuki T. Nat. Genet. 16:379-382(1997) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS CMH7 GLY-145 AND GLN-206.
[15]	"Sarcomere protein gene mutations in hypertrophic cardiomyopathy of the elderly." Niimura H., Patton K.K., McKenna W.J., Soults J., Maron B.J., Seidman J.G., Seidman C.E. Circulation 105:446-451(2002) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS CMH7 SER-82 AND ASN-196.
[16]	"Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations." Mogensen J., Kubo T., Duque M., Uribe W., Shaw A., Murphy R., Gimeno J.R., Elliott P., McKenna W.J. J. Clin. Invest. 111:209-216(2003) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS RCM1 GLN-144; TRP-145; THR-171; GLU-178; HIS-190 AND HIS-192.
[17]	"Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy." Richard P., Charron P., Carrier L., Ledeuil C., Cheav T., Pichereau C., Benaiche A., Isnard R., Dubourg O., Burban M., Gueffet J.-P., Millaire A., Desnos M., Schwartz K., Hainque B., Komajda M. Circulation 107:2227-2232(2003) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS CMH7 GLN-141; VAL-157; PRO-162; LYS-177 DEL; GLN-186 AND ASN-196.
[18]	Erratum Richard P., Charron P., Carrier L., Ledeuil C., Cheav T., Pichereau C., Benaiche A., Isnard R., Dubourg O., Burban M., Gueffet J.-P., Millaire A., Desnos M., Schwartz K., Hainque B., Komajda M. Circulation 109:3258-3258(2004)
[19]	"Mutation spectrum in a large cohort of unrelated consecutive patients with hypertrophic cardiomyopathy." Erdmann J., Daehmlow S., Wischke S., Senyuva M., Werner U., Raible J., Tanis N., Dyachenko S., Hummel M., Hetzer R., Regitz-Zagrosek V. Clin. Genet. 64:339-349(2003) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT CMH7 PHE-166.
[20]	"Novel mutation in cardiac troponin I in recessive idiopathic dilated cardiomyopathy." Murphy R.T., Mogensen J., Shaw A., Kubo T., Hughes S., McKenna W.J. Lancet 363:371-372(2004) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT CMD2A VAL-2.
[21]	"Compound and double mutations in patients with hypertrophic cardiomyopathy: implications for genetic testing and counselling." Ingles J., Doolan A., Chiu C., Seidman J., Seidman C., Semsarian C. J. Med. Genet. 42:E59-E59(2005) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS CMH7 PRO-162; GLN-162 AND HIS-204.
[22]	"Identification and functional characterization of cardiac troponin I as a novel disease gene in autosomal dominant dilated cardiomyopathy." Carballo S., Robinson P., Otway R., Fatkin D., Jongbloed J.D., de Jonge N., Blair E., van Tintelen J.P., Redwood C., Watkins H. Circ. Res. 105:375-382(2009) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS CMD1FF GLN-36 AND LYS-185.
[23]	"Clinical and mutational spectrum in a cohort of 105 unrelated patients with dilated cardiomyopathy." Millat G., Bouvagnet P., Chevalier P., Sebbag L., Dulac A., Dauphin C., Jouk P.S., Delrue M.A., Thambo J.B., Le Metayer P., Seronde M.F., Faivre L., Eicher J.C., Rousson R. Eur. J. Med. Genet. 54:E570-E575(2011) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT CMD1FF GLY-116.
+	Additional computationally mapped references.

Web resources

GeneReviews

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

X54163 mRNA. Translation: CAA38102.1.
M64247 mRNA. Translation: AAA16157.1.
X90780 Genomic DNA. Translation: CAA62301.1.

IPI

IPI00244346.

PIR

TPHUIC. A61229.

RefSeq

NP_000354.4. NM_000363.4.

UniGene

Hs.709179.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1J1D	X-ray	2.61	C/F	32-162	[»]
1J1E	X-ray	3.30	C/F	32-209	[»]
1LXF	NMR	-	I	148-164	[»]
1MXL	NMR	-	I	148-164	[»]
1OZS	NMR	-	B	129-148	[»]
2KGB	NMR	-	I	145-164	[»]
2KRD	NMR	-	I	148-164	[»]
2L1R	NMR	-	B	145-164	[»]

DisProt

DP00166.

ProteinModelPortal

P19429.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-34065N.

IntAct

P19429. 2 interactions.

MINT

MINT-2801556.

STRING

9606.ENSP00000341838.

PTM databases

PhosphoSite

P19429.

Polymorphism databases

DMDM

136213.

Proteomic databases

PaxDb

P19429.

PRIDE

P19429.

Protocols and materials databases

DNASU

7137.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000344887; ENSP00000341838; ENSG00000129991.

GeneID

7137.

KEGG

hsa:7137.

UCSC

uc002qjg.4. human.

Organism-specific databases

CTD

7137.

GeneCards

GC19M055663.

HGNC

HGNC:11947. TNNI3.

HPA

CAB018644.

MIM

115210. phenotype.
191044. gene.
611880. phenotype.
613286. phenotype.
613690. phenotype.

neXtProt

NX_P19429.

Orphanet

154. Familial isolated dilated cardiomyopathy.
155. Familial isolated hypertrophic cardiomyopathy.
99985. Familial restrictive cardiomyopathy type 1.

PharmGKB

PA36636.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG270363.

HOGENOM

HOG000293300.

HOVERGEN

HBG052737.

InParanoid

P19429.

KO

K12044.

OMA

RMYTCEG.

OrthoDB

EOG4001KH.

PhylomeDB

P19429.

Enzyme and pathway databases

Reactome

REACT_17044. Muscle contraction.

Gene expression databases

ArrayExpress

P19429.

Bgee

P19429.

CleanEx

HS_TNNC1.
HS_TNNI3.

Genevestigator

P19429.

GermOnline

ENSG00000129991. Homo sapiens.

Family and domain databases

InterPro

IPR001978. Troponin.
IPR021666. Troponin-I_N.
[Graphical view]

Pfam

PF00992. Troponin. 1 hit.
PF11636. Troponin-I_N. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

ChEMBL

CHEMBL1741177.

ChiTaRS

TNNI3. human.

EvolutionaryTrace

P19429.

GenomeRNAi

7137.

NextBio

27925.

SOURCE

Search...

Entry information

Entry name

TNNI3_HUMAN

Accession

Primary (citable) accession number: P19429

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 1, 1991
Last sequence update:	January 23, 2007
Last modified:	May 1, 2013
This is version 136 of the entry and version 3 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.