Nomenclature
Short Name:
TTN
Full Name:
Titin
Alias:
- Titin
- Connectin
Classification
Type:
Protein-serine/threonine kinase
Group:
CAMK
Family:
MLCK
SubFamily:
NA
Structure
Mol. Mass (Da):
631567
# Amino Acids:
5604
# mRNA Isoforms:
13
mRNA Isoforms:
3,994,625 Da (35991 AA; Q8WZ42-12); 3,831,069 Da (34484 AA; Q8WZ42-13); 3,829,846 Da (34475 AA; Q8WZ42-8); 3,816,030 Da (34350 AA; Q8WZ42); 3,805,708 Da (34258 AA; Q8WZ42-2); 3,734,648 Da (33615 AA; Q8WZ42-7); 3,716,027 Da (33445 AA; Q8WZ42-4); 3,713,600 Da (33423 AA; Q8WZ42-11); 3,653,085 Da (32900 AA; Q8WZ42-5); 3,013,957 Da (27118 AA; Q8WZ42-9); 3,006,755 Da (27051 AA; Q8WZ42-10); 2,992,939 Da (26926 AA; Q8WZ42-3)
4D Structure:
NA
1D Structure:
Subfamily Alignment
Domain Distribution:
| Start | End | Domain |
|---|---|---|
| 1979 | 2006 | Coiled-coil |
| 32178 | 32432 | Pkinase |
| 24917 | 24917 | phosphate |
| Titin Z |
Post-translation Modifications
For detailed information on phosphorylation of this kinase go to PhosphoNET
Acetylated:
K807, K1110, K1116, K1140, K1467, K2390, K3284, K4624, K6355, K6363, K8423, K8434, K8829, K8830, K9985, K9991, K10255, K10256, K10263, K10765, K10771, K10777, K10889, K10890, K10897, K11014, K11017, K11471, K11472, K11520, K11555, K11556, K12098, K12464, K12465, K12730, K12890, K13158, K13512, K13683, K14211, K14681, K16776, K17653, K18984, K19841, K20257, K20258, K20505, K20701, K21128, K21782, K22314, K22395, K22401, K23937, K23949, K28820, K30028, K30380, K33327, K33427, K33739.
Methylated:
K11528, K17400, R20057, K22427, K25000, K25023, R26651, K28031, K28034, K33281.
Serine phosphorylated:
S57, S214, S263, S265, S270, S282, S284, S291, S302, S306, S308, S314, S316, S528, S565, S755, S813, S819, S905, S1400, S1404, S1406, S1413, S1418, S1423, S1428, S1433, S1438, S1539, S1540, S1542, S1571, S1622, S2072, S2074, S2093, S2612, S3118, S3136, S3369, S3379, S3458, S3594, S3606, S3664, S3750, S3776, S3918, S4010, S4065, S4068, S4092, S4099, S4185, S4192, S4194, S4196, S4209, S4214, S4225, S4549, S4553, S4582, S4706, S4732, S5270, S5271, S5423, S5550, S5751, S5935, S6053, S6117, S6258, S6545, S6680, S6686, S6721, S6920, S7330, S7392, S7485, S8241, S8313, S8358, S8426, S8543, S8622, S8624, S8635, S9183, S9203, S10321, S10633, S11174, S11223, S11878, S12009, S12022, S12070, S12088, S12505, S12635, S12902, S12911, S12918, S12933, S12934, S13042, S13609, S13610, S13888, S14374, S14384, S14387, S14544, S14673, S14680, S14799, S15078, S15213, S15263, S15394, S15590, S15593, S15682, S15691, S16086, S16247, S16412, S16426, S16440, S16509, S16661, S16720, S16753, S17242, S17363, S17369, S17448, S18014, S18028, S18095, S18280, S18284, S18436, S18513, S18518, S18586, S18660, S19071, S19135, S19271, S19538, S19630, S19741, S19763, S19784, S19879, S19893, S19897, S20101, S20102, S20105, S20225, S20301, S20305, S20321, S20329, S20559, S20600, S20603, S20655, S20759, S20761, S20862, S20868, S20894, S21033, S21290, S21329, S21455, S21518, S21528, S21720, S21784, S21824, S21842, S22058, S22060, S22247, S22275, S22423, S22456, S22525, S22534, S22644, S22742, S22863, S22926, S22947, S23005, S23063, S23199, S23251, S23293, S23354, S23512, S23753, S24006, S24029, S24105, S24112, S24633, S24635, S24689, S24704, S24734, S24751, S25093, S25094, S25097, S25203, S25204, S25383, S25415, S25559, S25617, S25635, S25686, S25711, S25718, S25833, S25951, S26127, S26194, S26323, S26371, S26373, S26385, S26397, S26399, S26402, S26465, S26472, S26497, S26561, S26602, S26627, S26629, S27098, S27099, S27262, S27419, S27428, S27438, S27481, S27482, S27540, S27712, S27757, S27763, S27880, S27882, S28061, S28357, S28521, S28637, S28736, S28739, S28770, S28811, S28940, S29135, S29202, S29301, S29590, S29599, S29637, S29642, S29659, S29721, S29769, S29780, S29785, S29887, S29934, S29990, S30155, S30356, S33472, S33477, S33496, S33504, S33565, S33589, S33595, S33602, S33608, S33614, S33618, S33624, S33791, S33938, S33942, S33976, S34266, S34298.
Threonine phosphorylated:
T204, T206, T219, T267, T300, T411, T520, T559, T579, T617, T663, T817, T1124, T1205, T1546, T1629, T1785, T1833, T2060, T2063, T2190, T2193, T2611, T2695, T2760, T3022, T3119, T3128, T3137, T3249, T3354, T3934, T4184, T4293, T4298, T4725, T4852, T5748, T5750, T6086, T7230, T8544, T9151, T9207, T9970, T10313, T10316, T10581, T11532, T11922, T11932, T11969, T12007, T12490, T12545, T12593, T12600, T12866, T12909, T12913, T14099, T14105, T14281, T14372, T14527, T14534, T14674, T15023, T15396, T15781, T16062, T16350, T16434, T16581, T16819, T17202, T17204, T17576, T17996, T18195, T18256, T18388, T18390, T18422, T18505, T18511, T19139, T19272, T19355, T19743, T19762, T19856, T19889, T19899, T19908, T20112, T20253, T20261, T20307, T20462, T20483, T20527, T20528, T20637, T20653, T20733, T20762, T20764, T20873, T20879, T20983, T21007, T21060, T21061, T21378, T21511, T21650, T21651, T21667, T21794, T21837, T21843, T21845, T21987, T22066, T22191, T22310, T22419, T22539, T22637, T22647, T22749, T23083, T23085, T23133, T23210, T23225, T23726, T23898, T24012, T24219, T24239, T24402, T24407, T24465, T24469, T24542, T24694, T24702, T24708, T24835, T24980, T25282, T25283, T25375, T25385, T25687, T25716, T25722, T25791, T25841, T25939, T25993, T26115, T26133, T26143, T26365, T26366, T26375, T26404, T26471, T26571, T26784, T27059, T27217, T27255, T27266, T27436, T27477, T27484, T27545, T27554, T27562, T27563, T27752, T28480, T28841, T29123, T29243, T29270, T29272, T29593, T29626, T29648, T29698, T29713, T29772, T29875, T29878, T29929, T29938, T29985, T30009, T30443, T30456, T30516, T30532, T30605, T30655, T30713, T30716, T30718, T30724, T30728, T30744, T31011, T31012, T31020, T31022, T31051, T31084, T31269, T31312, T31313, T31314, T31446, T31514, T31516, T31611, T31764, T31803, T32164, T32171, T32265, T32313, T32599, T32609, T32649, T32667, T32678, T32691, T32752, T32839, T32855, T32998, T33089, T33094, T33137, T33138, T33169, T33172, T33205, T33231, T33237, T33279, T33391, T33478, T33484, T33485, T33574, T33576, T33626, T33633, T33941, T33973, T34274.
Tyrosine phosphorylated:
Y1114, Y1126, Y1189, Y1211, Y1214, Y1218, Y1260, Y1325, Y1380, Y1867, Y1875, Y1891, Y1896, Y2010, Y2112, Y2208, Y2443, Y2479, Y2753, Y2762, Y3052, Y3110, Y3127, Y3273, Y3378, Y3407, Y3666, Y4126, Y4424, Y4548, Y4714, Y5086, Y6059, Y6478, Y6608, Y6682, Y7892, Y7981, Y8212, Y8360, Y8490, Y8790, Y8804, Y8868, Y9153, Y9211, Y9525, Y9618, Y9745, Y9849, Y9983, Y10672, Y10678, Y10680, Y10686, Y10692, Y10695, Y10703, Y10706, Y11731, Y12336, Y12591, Y12946, Y13156, Y13257, Y13435, Y13459, Y13524, Y13713, Y13783, Y14376, Y14790, Y14869, Y15009, Y15080, Y15384, Y15476, Y15491, Y15789, Y15988, Y16230, Y16422, Y16442, Y16506, Y17121, Y17203, Y17224, Y17418, Y17474, Y17578, Y17595, Y17714, Y17919, Y18078, Y18254, Y18316, Y18508, Y18665, Y18666, Y18997, Y18998, Y19045, Y19087, Y19098, Y19273, Y19320, Y19695, Y19696, Y19760, Y19764, Y19796, Y19850, Y19895, Y19896, Y20078, Y20089, Y20094, Y20110, Y20178, Y20328, Y20395, Y20412, Y20485, Y20508, Y20514, Y20525, Y20599, Y20610, Y20686, Y20731, Y20793, Y20845, Y20867, Y20919, Y21083, Y21226, Y21235, Y21377, Y21479, Y21853, Y21864, Y21874, Y21998, Y22063, Y22256, Y22309, Y22562, Y22579, Y22641, Y22652, Y22743, Y22754, Y22948, Y22949, Y22958, Y23238, Y23253, Y23263, Y23400, Y23495, Y23644, Y23734, Y23755, Y23763, Y24007, Y24030, Y24031, Y24040, Y24285, Y24330, Y24347, Y24482, Y24726, Y24816, Y24837, Y24838, Y25004, Y25089, Y25113, Y25412, Y25427, Y25502, Y25555, Y25564, Y25747, Y25788, Y25809, Y25826, Y25928, Y26160, Y26195, Y26196, Y26484, Y26494, Y26552, Y26589, Y26890, Y27159, Y27263, Y27274, Y27275, Y27414, Y27523, Y27567, Y27973, Y28063, Y28065, Y28154, Y28165, Y28166, Y28245, Y28514, Y28664, Y28743, Y28759, Y28790, Y28840, Y28851, Y29014, Y29240, Y29445, Y29446, Y29461, Y29553, Y29645, Y29777, Y29792, Y29827, Y29838, Y29843, Y29900, Y29939, Y30025, Y30147, Y30220, Y30223, Y30294, Y30316, Y30442, Y30462, Y30535, Y30829, Y30929, Y31019, Y31063, Y31146, Y31203, Y31225, Y31291, Y31292, Y31316, Y31494, Y31559, Y31565, Y31566, Y31610, Y31721, Y31722, Y31787, Y31868, Y31902, Y31911, Y32001, Y32151, Y32175, Y32178, Y32341, Y32580, Y32592, Y32594, Y32595, Y32624, Y32629, Y32651, Y32698, Y32793, Y32869, Y32899, Y32907, Y32937, Y32963, Y33003, Y33006, Y33007, Y33069, Y33087, Y33090, Y33102, Y33227, Y33335, Y33421, Y33500, Y34010.
Ubiquitinated:
K10492, K10922, K13915, K15135, K15149, K20304, K20315, K22934.
Distribution
Based on gene microarray analysis from the NCBI
Human Tissue Distribution
% Max Expression:
Mean Expression:
Number of Samples:
Standard Deviation:
% Max Expression:
Mean Expression:
Number of Samples:
Standard Deviation:
10
1189
58
1406
0.3
37
23
82
2
200
187
515
1
108
362
375
4
407
65
305
0.5
52
89
152
0.4
50
75
172
62
7081
213
8222
1
127
16
172
1
108
285
479
2
194
176
837
3
369
317
559
2
234
200
459
0.4
44
17
99
2
269
208
504
0.2
22
35
42
3
385
467
1833
13
1512
201
2309
100
11346
307
11847
4
399
199
302
1
140
204
438
2
210
208
449
1
151
195
391
3
369
204
341
2
205
208
408
5
586
306
1333
11
1200
209
2516
2
229
198
770
2
190
201
769
1
145
70
126
5
604
54
252
9
993
48
4298
2
172
136
510
6
689
161
624
0.9
101
123
127
Evolution
Species Conservation
PhosphoNET % Identity:
PhosphoNET % Similarity:
Homologene %
Identity:
PhosphoNET % Identity:
PhosphoNET % Similarity:
Homologene %
Identity:
100
100
100
0
0
95
-
-
95
-
-
90
-
-
93
-
-
93
-
-
-
-
-
92
-
-
82
-
-
-
-
-
-
-
-
75
-
-
78
-
-
64
-
-
-
-
-
25
-
-
-
-
-
27
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
For a wider analysis go to PhosphoNET Evolution in PhosphoNET
Regulation
Activation:
NA
Inhibition:
NA
Synthesis:
NA
Degradation:
NA
Known Downstream Substrates
For further details on these substrates click on the Substrate Short Name or UniProt ID. Phosphosite Location is hyperlinked to PhosphoNET
predictions.
Based on in vitro and/or in vivo phosphorylation data
| Substrate Short Name | UniProt ID (Human) | Phosphosite Location | Phosphosite Sequence | Effect of Phosphorylation |
|---|
| Telethonin | O15273 | S157 | GALRRSLSRSMSQEA |
Protein Kinase Specificity
Matrix of observed frequency (%) of amino acids in aligned protein substrate phosphosites
Matrix Type:
Predicted from the application of the Kinexus Kinase Substrate Predictor Version 2.0 algorithm, which was trained with over 10,000 kinase-protein substrate pairs and 8,000 kinase-peptide substrate pairs.
Domain #:
1
Disease Linkage
General Disease Association:
Cancer, cardiomuscular disorders
Specific Diseases (Non-cancerous):
TTN-related dilated Cardiomyopathy; TTN-related familial hypertrophic cardiomyopathy; Hereditary myopathy with early respiratory failure; Familial hypertrophic cardiomyopathy; Hypertrophic cardiomyopathy; Cardiomyopathy, dilated, 1g (CMD1G); Udd distal myopathy; Salih myopathy; Centronuclear myopathy; Respiratory failure; Myasthenia gravis; Distal myopathy Markesbery-Griggs type; Limb-Girdle muscular dystrophy Type 2j (LGMD2J); Rippling muscle disease; Meconium aspiration syndrome; Diastolic heart Failure; Newborn respiratory Distress syndrome; Diastolic heart failure; Newborn respiratory distress syndrome; Morvan's fibrillary chorea; Cardiomyopathy, familial hypertrophic, 9 (CMH9); Cardiomyopathy, dilated, 1w; Rigid spine syndrome; Familial isolated Arrhythmogenic ventricular dysplasia, right dominant form; Familial isolated arrhythmogenic ventricular dysplasia, Biventricular form; Familial isolated arrhythmogenic ventricular dysplasia, left dominant form; Casp10-related autoimmune lymphoproliferative syndrome; Antenatal multiminicore disease with arthrogryposis multiplex congenita
Comments:
The R279W substitution in TTN is associated with hereditary myopathy with early respiratory failure, which is an adult-onset myopathy with early respiratory muscle involvement. R740L mutation is associated with cardiomyopathy, familial hypertrophic 9, which is a hereditary heart disorder characterized by ventricular hypertrophy.
Specific Cancer Types:
Rhabdomyosarcomas (RSC); scleroderma
Comments:
TTN SNPs have been identified and may be critical in the pathogenesis of rhabdomyosarcomas.
Mutagenesis Experiments:
Insertional mutagenesis studies in mice have not yet revealed a role for this protein kinase in mouse cancer oncogenesis.
Mutation Rate in All Cancers:
Percent mutation rates per 100 amino acids length in human cancers: 0.25 % in 24507 diverse cancer specimens. This rate is 3.3-fold higher than the average rate of 0.075 % calculated for human protein kinases in general.
Mutation Rate in Specific Cancers:
Highest percent mutation rates per 100 amino acids length in human cancers: 0.75 % in 555 stomach cancers tested; 0.67 % in 864 skin cancers tested; 0.66 % in 1248 large intestine cancers tested; 0.54 % in 710 oesophagus cancers tested; 0.46 % in 273 cervix cancers tested; 0.4 % in 1608 lung cancers tested; 0.4 % in 1512 liver cancers tested; 0.36 % in 10 peritoneum cancers tested; 0.34 % in 548 urinary tract cancers tested; 0.29 % in 603 endometrium cancers tested; 0.28 % in 238 bone cancers tested; 0.26 % in 1289 breast cancers tested; 0.25 % in 942 upper aerodigestive tract cancers tested; 0.25 % in 1253 kidney cancers tested; 0.23 % in 807 ovary cancers tested; 0.21 % in 1459 pancreas cancers tested; 0.14 % in 65 Meninges cancers tested; 0.13 % in 2030 central nervous system cancers tested; 0.13 % in 127 biliary tract cancers tested; 0.12 % in 881 prostate cancers tested; 0.07 % in 382 soft tissue cancers tested; 0.06 % in 558 thyroid cancers tested; 0.06 % in 441 autonomic ganglia cancers tested; 0.06 % in 1982 haematopoietic and lymphoid cancers tested.
Frequency of Mutated Sites:
Most frequent mutations with the number of reports indicated in brackets: I27048M (16).
Comments:
Over 80 deletions, over 24 insertions, and 3 complex mutations are noted on the COSMIC website.