Reviewed, UniProtKB/Swiss-Prot Q8WZ42 (TITIN_HUMAN)

Names and origin

Protein names

Titin
Also known as:
     EC 2.7.11.1
     Connectin
     Rhabdomyosarcoma antigen MU-RMS-40.14

Gene names

Name:

TTN

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein existence

Evidence at protein level.

General annotation (Comments)

Function	Key component in the assembly and functioning of vertebrate striated muscles. By providing connections at the level of individual microfilaments, it contributes to the fine balance of forces between the two halves of the sarcomere. The size and extensibility of the cross-links are the main determinants of sarcomere extensibility properties of muscle. In non-muscle cells, seems to play a role in chromosome condensation and chromosome segregation during mitosis. Might link the lamina network to chromatin or nuclear actin, or both during interphase.
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Cofactor	Magnesium.
Enzyme regulation	Full activation of the protein kinase domain requires both phosphorylation of Tyr-32341, preventing it from blocking the catalytic aspartate residue, and binding of Ca/CALM to the C-terminal regulatory tail of the molecule which results in ATP binding to the kinase.
Subunit structure	Interacts with MYOM1, MYOM2, tropomyosin and myosin. Interacts with actin, primarily via the PEVK domains and with MYPN By similarity. Interacts with FHL2, NEB, CRYAB, LMNA/lamin-A and LMNB/lamin-B. Interacts with TCAP/telethonin and/or ANK1 isoform Mu17/ank1.5, via the first two N-terminal immunoglobulin domains. Interacts with TRIM63 and TRIM55, through several domains including immunoglobulin domains 141 and 142. Interacts with ANKRD1, ANKRD2 and ANKRD23, via the region between immunoglobulin domains 77 and 78 and interacts with CAPN3, via immunoglobulin domain 79. Interacts with NBR1 through the protein kinase domain. Interacts with CALM/calmodulin. Isoform 8 interacts with OBSCN isoform 3.
Subcellular location	Cytoplasm Probable. Nucleus.
Tissue specificity	Isoform 3, isoform 7 and isoform 8 are expressed in cardiac muscle. Isoform 4 is expressed in vertebrate skeletal muscle. Isoform 6 is expressed in cardiac tissues.
Domain	ZIS1 and ZIS5 regions contain multiple SPXR consensus sites for ERK- and CDK-like protein kinases as well as multiple SP motifs. ZIS1 could adopt a closed conformation which would block the TCAP-binding site. The PEVK region may serve as an entropic spring of a chain of structural folds and may also be an interaction site to other myofilament proteins to form interfilament connectivity in the sarcomere.
Post-translational modification	Autophosphorylated By similarity. Phosphorylated upon DNA damage, probably by ATM or ATR.
Involvement in disease	Defects in TTN are the cause of hereditary myopathy with early respiratory failure (HMERF) [MIM:603689]; also known as Edstrom myopathy. HMERF is an autosomal dominant, adult-onset myopathy with early respiratory muscle involvement. Defects in TTN are the cause of cardiomyopathy familial hypertrophic type 9 (CMH9) [MIM:188840]. Familial hypertrophic cardiomyopathy is 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. Defects in TTN are the cause of cardiomyopathy dilated type 1G (CMD1G) [MIM:604145]. Dilated cardiomyopathy is a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. Defects in TTN are the cause of tardive tibial muscular dystrophy (TMD) [MIM:600334]; also known as Udd myopathy. TMD is an autosomal dominant, late-onset distal myopathy. Muscle weakness and atrophy are usually confined to the anterior compartment of the lower leg, in particular the tibialis anterior muscle. Clinical symptoms usually occur at age 35-45 years or much later. Defects in TTN are the cause of limb-girdle muscular dystrophy type 2J (LGMD2J) [MIM:608807]. LGMD2J is an autosomal recessive degenerative myopathy characterized by progressive weakness of the pelvic and shoulder girdle muscles. Severe disability is observed within 20 years of onset. Defects in TTN are the cause of early-onset myopathy with fatal cardiomyopathy (EOMFC) [MIM:611705]. Early-onset myopathies are inherited muscle disorders that manifest typically from birth or infancy with hypotonia, muscle weakness, and delayed motor development. EOMFC is a titinopathy that, in contrast with the previously described examples, involves both heart and skeletal muscle, has a congenital onset, and is purely recessive. This phenotype is due to homozygous out-of-frame TTN deletions, which lead to a total absence of titin's C-terminal end from striated muscles and to secondary CAPN3 depletion.
Miscellaneous	In some isoforms, after the PEVK repeat region there is a long PEVK duplicated region. On account of this region, it has been very difficult to sequence the whole protein. The length of this region (ranging from 183 to 2174 residues), may be a key elastic element of titin.
Sequence similarities	Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. Contains 132 fibronectin type-III domains. Contains 152 Ig-like (immunoglobulin-like) domains. Contains 19 Kelch repeats. Contains 1 protein kinase domain. Contains 17 RCC1 repeats. Contains 14 TPR repeats. Contains 15 WD repeats.
Sequence caution	AAH58824.1 sequence differs from that shown. Reason: Miscellaneous discrepancy. Contaminating sequence. Potential poly-A sequence starting in position 553. AAH70170.1 sequence differs from that shown. Reason: Miscellaneous discrepancy. Contaminating sequence. Potential poly-A sequence starting in position 627.

Ontologies

Keywords
Cellular component	Cytoplasm Nucleus
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Cardiomyopathy Disease mutation Limb-girdle muscular dystrophy
Domain	Coiled coil Immunoglobulin domain Kelch repeat Repeat TPR repeat WD repeat
Ligand	ATP-binding Calcium Calmodulin-binding Magnesium Metal-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein Ubl conjugation
Technical term	3D-structure
Gene Ontology (GO)
Biological process	mitosis Traceable author statement. Source: UniProtKB myofibril assembly Ref.30 Inferred from mutant phenotype. Source: UniProtKB protein amino acid autophosphorylation Ref.30 Inferred from mutant phenotype. Source: UniProtKB striated muscle contraction Ref.1 Traceable author statement. Source: UniProtKB
Cellular component	Z disc Ref.6 Inferred from direct assay. Source: UniProtKB condensed nuclear chromosome Traceable author statement. Source: UniProtKB
Molecular function	ATP binding Ref.30 Traceable author statement. Source: UniProtKB alpha-actinin binding Traceable author statement. Source: UniProtKB calmodulin binding Traceable author statement. Source: UniProtKB identical protein binding Ref.30 Inferred from physical interaction. Source: UniProtKB myosin binding Ref.3 Traceable author statement. Source: UniProtKB protein serine/threonine kinase activity Ref.30 Inferred from direct assay. Source: UniProtKB structural constituent of muscle Ref.1 Traceable author statement. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
ACTN2	P35609	5	EBI-681210,EBI-77797
OBSCN	Q5VST9	3	EBI-681210,EBI-941850
TCAP	O15273	1	EBI-681210,EBI-954089

Alternative products

This entry describes 8 isoforms produced by alternative splicing. Notes: A number of isoforms may be produced, ranging from 27000 to 33000 residues in different striated muscle tissues, the size of the full length protein may be up to 38138 residues. [Align] [Select]

Isoform 1 (identifier: Q8WZ42-1)
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.
Notes: No experimental confirmation available.

Isoform 2 (identifier: Q8WZ42-2)
The sequence of this isoform differs from the canonical sequence as follows:
     555-646: Missing.
Notes: No experimental confirmation available.

Isoform 3 (identifier: Q8WZ42-3)
Also known as Small cardiac N2-B;
The sequence of this isoform differs from the canonical sequence as follows:
     556-601: Missing.
     4474-11851: Missing.

Isoform 4 (identifier: Q8WZ42-4)
Also known as Soleus;
The sequence of this isoform differs from the canonical sequence as follows:
     3454-4380: Missing.
     11507-11507 E → EVFEEPEESPSAPPKKPEVPPVR
Notes: No experimental confirmation available.

Isoform 5 (identifier: Q8WZ42-5)
The sequence of this isoform differs from the canonical sequence as follows:
     10382-10645: Missing.
     10742-10931: Missing.
     11015-11163: Missing.
     11223-11852: Missing.
     11985-12201: Missing.
Notes: No experimental confirmation available.

Isoform 6 (identifier: Q8WZ42-6)
Also known as Small cardiac novex-3;
The sequence of this isoform differs from the canonical sequence as follows:
     3455-5604 FSSSFLSAEE...VLDLIIPPSF → LFSEGESEHS...AESFAALTLT
     5605-34350: Missing.
Notes: Phosphorylated on Thr-5304 and Ser-5306.

Isoform 7 (identifier: Q8WZ42-7)
Also known as Cardiac novex-2;
The sequence of this isoform differs from the canonical sequence as follows:
     3435-3645 APESILHERI...LPAIFEYTVV → VQALDRQSSG...IEQEIEMEMK
     3646-4380: Missing.

Isoform 8 (identifier: Q8WZ42-8)
Also known as Cardiac novex-1;
The sequence of this isoform differs from the canonical sequence as follows:
     3434-3434 E → GFSKFEENTS...CAATLTVTPK

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view
Molecule processing
	Chain	1 – 34350	34350	Titin
Regions
	Domain	6 – 96	91	Ig-like 1
	Domain	104 – 192	89	Ig-like 2
	Repeat	417 – 462	46	Z-repeat 1
	Repeat	466 – 511	46	Z-repeat 2
	Repeat	512 – 554	43	Z-repeat 3
	Repeat	555 – 600	46	Z-repeat 4
	Repeat	601 – 646	46	Z-repeat 5
	Repeat	647 – 691	45	Z-repeat 6
	Repeat	692 – 740	49	Z-repeat 7
	Domain	943 – 1031	89	Ig-like 3
	Domain	1082 – 1172	91	Ig-like 4
	Domain	1291 – 1382	92	Ig-like 5
	Domain	1457 – 1546	90	Ig-like 6
	Domain	1556 – 1646	91	Ig-like 7
	Domain	1703 – 1793	91	Ig-like 8
	Domain	1841 – 1928	88	Ig-like 9
	Domain	2078 – 2167	90	Ig-like 10
	Repeat	2089 – 2122	34	TPR 1
	Domain	2171 – 2262	92	Ig-like 11
	Domain	2264 – 2354	91	Ig-like 12
	Domain	2353 – 2443	91	Ig-like 13
	Domain	2430 – 2529	100	Ig-like 14
	Domain	2620 – 2703	84	Ig-like 15
	Repeat	2804 – 2838	35	TPR 2
	Domain	2880 – 2965	86	Ig-like 16
	Domain	2968 – 3050	83	Ig-like 17
	Repeat	3022 – 3062	41	WD 1
	Domain	3058 – 3141	84	Ig-like 18
	Domain	3239 – 3327	89	Ig-like 19
	Domain	3344 – 3432	89	Ig-like 20
	Domain	3503 – 3586	84	Ig-like 21
	Domain	3621 – 3712	92	Ig-like 22
	Repeat	4168 – 4203	36	TPR 3
	Domain	4289 – 4376	88	Ig-like 23
	Domain	4383 – 4471	89	Ig-like 24
	Domain	4478 – 4566	89	Ig-like 25
	Domain	4571 – 4659	89	Ig-like 26
	Domain	4664 – 4753	90	Ig-like 27
	Domain	4758 – 4846	89	Ig-like 28
	Domain	4851 – 4936	86	Ig-like 29
	Repeat	4860 – 4904	45	Kelch 1
	Domain	4943 – 5032	90	Ig-like 30
	Domain	5040 – 5128	89	Ig-like 31