ライフサイエンスコーパス: titin

1 or altered crossbridge recruitment (cMyBP-C/titin).

2 ion suggests a neutral effect in the case of titin.

3 matrix fibrillar collagen and cardiomyocyte titin.

4 rdiac myosin-binding protein C (cMyBP-C) and titin.

5 oth effects favor a more extensible state of titin.

6 ngs to the relatively stiff A-band region of titin.

7 comeric stiffening is the sarcomeric protein titin.

8 the heart, but has not been known to target titin.

9 ed from the striated muscle-specific protein titin.

10 TnI), myosin binding protein-C (cMyBP-C) and titin.

11 e tandem insertion) that altered full-length titin.

12 ing Smyd2, Hsp90, and the sarcomeric protein titin.

13 ne, glutamate, valine, and lysine) region of titin.

14 n of alpha-actinin binds to the Z-repeats of titin.

15 xposed to mechanical forces, such as cardiac titin.

16 njection, made up approximately 45% of total titin.

17 sively increasing mechanical stability makes titin a variable viscosity damper, the spatially randomi

18 d cardiomyopathy were overrepresented in the titin A-band but were absent from the Z-disk and M-band

19 For the mechanostable muscle protein titin, a highly ductile model reconciles data over 10 or

20 Titin, a sarcomeric protein expressed primarily in stria

21 n blotting showed more pronounced C-terminal titin abnormality than expected for heterozygous proband

22 lpha-B crystallin probably through relief of titin aggregation.

23 effect of baseline phosphorylation and from titin aggregation.

24 Along the way we distinguish among titin alterations in systolic and in diastolic heart fai

25 actions cooperate to ensure long-term stable titin anchoring while allowing the individual components

26 unoglobulin (Ig) domain of the giant protein titin and a frequent target of disease-linked mutations.

27 and after KCl-KI treatment, which unanchors titin and allows contributions of titin and extracellula

28 al heart development and function, including Titin and calcium/calmodulin-dependent protein kinase II

29 g with known pathological splice variants of Titin and Camk2d genes by Day 24 of cardiogenesis.

30 athionylation may regulate the elasticity of titin and cardiac tissue.

31 unanchors titin and allows contributions of titin and extracellular matrix to Fpassive to be discern

32 id A, Apolipoprotein A1, C-reactive protein, Titin and Haptoglobin, were found to be sequentially alt

33 Cardiomyocytes with a less distensible titin and interstitial collagen contribute to the high d

34 gulation of thick filament length depends on titin and is critical for maintaining muscle health.

35 ible locations of the 39 A-spaced domains of titin and the cardiac isoform of myosin-binding protein-

36 exon has sequence similarity to I-connectin/Titin and was acquired after the first round of whole-ge

37 nabling TCR cross-recognition of MAGE-A3 and Titin, and applied the resulting data to rationally desi

38 muscle contraction, interacting with myosin, titin, and possibly actin.

39 rats that express a giant splice isoform of titin, and subjected the muscles to stretch from 2.0 to

40 uted homogenously along the entire length of titin, and this homogeneity is maintained with increasin

41 ng tension because of hypophosphorylation of titin; and 5) both stiff cardiomyocytes and interstitial

42 immunoblotting using phosphoserine-specific titin-antibodies.

43 and DKO cardiomyocytes, an effect blunted by titin antibody pretreatment.

44 found to be high, relative to that of I-band titin ( approximately 40-fold higher) but low, relative

45 -transmitting protein domains of filamin and titin are kinetically ductile when pulled from their two

46 -state lifetime distributions of full-length titin are sensitive to force.

47 ating mutations in the giant sarcomeric gene Titin are the most common type of genetic alteration in

48 A main theme is the evolving role of titin as a modulator of contraction.

49 either cTnI S23/24 variant, leaving cMyBP-C/titin as PKA targets.

50 icating the novel A178D missense mutation in titin as the cause of a highly penetrant familial cardio

51 assess the effect of upregulating compliant titin at the cellular and organ levels.

52 Findings disproved that titin at the IA junction is crucial for thick filament l

53 We conclude that titin-based cardiac myocyte stiffening acutely after MI

54 matrix-based passive stiffness, supporting a titin-based mechanism for in vivo diastolic dysfunction.

55 However, titin-based muscle stiffness was reduced in the mice tha

56 descending coronary artery ligature restored titin-based myocyte tension after MI, suggesting that MI

57 Increased titin-based passive stiffness is sufficient to cause dia

58 iac myocytes before and after elimination of titin-based stiffness.

59 gth is controlled involves the giant protein titin, but no conclusive support for this hypothesis exi

60 es were identified within the PEVK-domain of titin by quantitative mass spectrometry and confirmed in

61 Telethonin (also known as titin-cap or t-cap) is a muscle-specific protein whose m

62 such as cardiac myosin binding protein-C or titin, cause familial hypertrophic cardiomyopathies, it

63 h of contacts between telethonin and the two titin chains, and secondarily by the timescales of confo

64 rdiac sample from an RBM20 mutation carrier, titin circRNA production was severely altered.

65 ss of RBM20 caused only a specific subset of titin circRNAs to be lost.

66 ice and show that they completely lack these titin circRNAs.

67 However, how increasing titin compliance impacts global cardiac function require

68 Though encoded by only one gene, titin comprises hundreds of exons and has the potential

69 oteins in the vicinity of the cardiac Z disk/titin cytoskeleton.

70 s to determine total, collagen-dependent and titin-dependent stiffness (differential extraction assay

71 myocardial stiffness; collagen-dependent and titin-dependent stiffness were increased.

72 etic peptide, total, collagen-dependent, and titin-dependent stiffness, insoluble collagen, increased

73 tributions and mechanisms underlying loss of titin distensibility were assessed in failing human hear

74 Cardiomyocytes were stretched to investigate titin distensibility.

75 failing human myocardium because of reduced titin distensibility.

76 quence and hyperphosphorylation of the PEVK (titin domain rich in proline, glutamate, valine, and lys

77 ation, titin elastic recoil and refolding of titin domains as an energy source, and Ca(2+)-dependent

78 excursions inside telethonin and the pulled titin domains.

79 s the basis for length-dependent activation, titin elastic recoil and refolding of titin domains as a

80 Taken together, titin emerges as a linker element between passive and ac

81 e used by Rbm20 to skip different subsets of titin exons, and the splicing pathway selected depended

82 of specific circular RNAs derived from Ttn (Titin), Fhod3 (Formin homology 2 domain containing 3), a

83 The giant protein titin forms a unique filament network in cardiomyocytes,

84 unity remains to extend our understanding of titin function in striated muscle.

85 Several patients with previously reported titin gene (TTN) mutations causing tibial muscular dystr

86 Titin gene (TTN) mutations have been described in eight

87 ecent insight into the mechanisms behind how titin gene mutations cause hereditary cardiomyopathy and

88 l system for evaluating the pathogenicity of titin gene variants.

89 ntified 80 circRNAs to be expressed from the titin gene, a gene that is known to undergo highly compl

90 of a conserved internal promoter within the Titin gene, we sought to develop an integrative statisti

91 rcRNAs that originate from the I-band of the titin gene.

92 itin N2BA/N2B isoform ratio and there was no titin haploinsufficiency.

93 Titin has been identified as a target of S-glutathionyla

94 Experimentally upregulating compliant titins has been suggested as a therapeutic for lowering

95 TTN, the gene encoding the sarcomere protein titin, has been insufficiently analyzed for cardiomyopat

96 Titin holds promise as a therapeutic target for heart fa

97 FpEF depends on changes in both collagen and titin homeostasis.

98 ing the localization of Projectin protein, a titin homolog, in sarcomeres as well as muscle morpholog

99 tensive HFpEF, LA cardiomyocyte hypertrophy, titin hyperphosphorylation, and microvascular dysfunctio

100 Titin hypophosphorylation importantly contributed to the

101 , which was largely (+/-80%) attributable to titin hypophosphorylation.

102 eling pulling experimental data for I91 from titin I-band (PDB ID: 1TIT) and ubiquitin (PDB ID: 1UBQ)

103 structs composed of up to four copies of the Titin I27 domain or its mutant I27* (I59E).

104 mic force spectroscopy of single dextran and titin I27 molecules using small-amplitude and low-freque

105 By chemically coupling a titin I27 polyprotein to the motor domain of myosin, we

106 model that well describes the aggregation of Titin I27, an immunoglobulin-like domain.

107 nd that ClpXP and ClpAP unfold the wild-type titin(I27) domain and a destabilized variant far more ra

108 substrates containing multiple copies of the titin(I27) domain during degradation initiated from the

109 We conclude that aggregation of unfolded titin Ig domains stiffens myocytes and that sHSPs transl

110 Promoting titin Ig unfolding in cardiomyocytes caused elevated sti

111 ndent and promoted by factors that increased titin Ig unfolding, including sarcomere stretch and the

112 al tandem Ig segment of the spring region of titin (IG KO).

113 Here, we show that mechanical unfolding of titin immunoglobulin (Ig) domains exposes buried cystein

114 tudies of ttn(xu071) uncovered a function of titin in guiding the assembly of nascent myofibrils from

115 the effects of increasing the compliance of titin in mice with diastolic dysfunction.

116 n this review, we cover the roles of cardiac titin in normal and failing hearts, with a special empha

117 Increasing the compliance of titin in the heart has become possible recently through

118 Topics include strain-sensing via titin in the sarcomeric A-band as the basis for length-d

119 One of the main candidates for anchoring titin in the Z-disk is the actin cross-linker alpha-acti

120 nt evidence has implicated the giant protein titin in this cellular process, possibly by positioning

121 3-mediated cleavage of its in vivo substrate titin in tissue extracts.

122 stigate the effect of upregulating compliant titins in a novel mouse model with a genetically altered

123 20(DeltaRRM)-raloxifene mice expressed large titins in the hearts, called supercompliant titin (N2BAs

124 ion of the I-band-A-band junction (IAjxn) in titin increases strain on the spring region and causes a

125 phorylation by PKA of either cTnI or cMyBP-C/titin independently reduces the pCa(50) preferentially a

126 By mimicking the structure/function model of titin, integration of dynamic cucurbit[8]uril mediated h

127 The giant elastic protein titin is a determinant factor in how much blood fills th

128 Titin is a giant filamentous protein of the muscle sarco

129 Titin is a large filamentous protein that is responsible

130 Titin is not only important in diastolic but also in sys

131 g between the immunoglobulin-like domains of titin is prevented.

132 Titin is the first sarcomeric protein linked to arrhythm

133 Titin is the main determinant of cellular passive stiffn

134 A missense mutation in the giant protein titin is the only plausible disease-causing variant that

135 ch (PEVK) domain of the giant muscle protein titin is thought to be an intrinsically unstructured ran

136 TTN, which encodes titin, is also a major human disease gene.

137 lagen assays (biochemistry or histology), or titin isoform and phosphorylation assays.

138 No alterations were observed in titin isoform composition (N2BA/N2B ratio: PAH, 0.78 +/-

139 Therefore, we investigated titin isoform composition and phosphorylation.

140 ssive tension that was not due to changes in titin isoform composition or phosphorylation.

141 Total fibrosis and titin isoform composition were similar between groups; h

142 Titin isoform expression was evaluated with agarose gels

143 m20) as the underlying cause of pathological titin isoform expression.

144 sarcomeric protein expression, modification, titin isoform shift, and contractile behavior of cardiom

145 myofilament proteins and increased compliant titin isoform, may explain the increase in passive force

146 We discuss the importance of titin-isoform shifts and titin phosphorylation, as well

147 Inhibition of RBM20 leads to super compliant titin isoforms (N2BAsc) that reduce passive stiffness.

148 t time a benefit from upregulating compliant titin isoforms in a murine model with HFpEF-like symptom

149 Increased expression of compliant titin isoforms was observed only in mild RV dysfunction,

150 of RBM20 in Ttn(DeltaIAjxn) mice, compliant titin isoforms were expressed, diastolic function was no

151 Myocardial collagen, collagen cross-linking, titin isoforms, and phosphorylation were also determined

152 arcomere stretch and the expression of stiff titin isoforms.

153 Using titin kinase and green fluorescent protein, we show that

154 ignificant homology with the force-activated titin kinase, smMLCK is suspected to be also regulatable

155 interaction with sarcomeric proteins such as titin, lays a foundation for studying the impact of path

156 the mutation markedly impairs binding to the titin ligand telethonin.

157 ther, we compare invertebrate and vertebrate titin-like kinases and identify variations in the regula

158 Titin-like kinases are an important class of cytoskeleta

159 Titin may thereby provide complex safety mechanims for p

160 ain is sufficient to prevent misfolding of a titin mechanical reporter.

161 S-glutathionylation of cryptic cysteines in titin mediates mechanochemical modulation of the elastic

162 Here we show that an engineered titin-mimicking protein is able to spontaneously dimeriz

163 the FINmaj TMD mutation and the novel A-band titin missense mutation showed a phenotype completely di

164 Large numbers of rare and unique titin missense variants have been discovered in both hea

165 It furthermore highlights that rare titin missense variants, currently often ignored or left

166 for myocardial DD of collagen deposition and titin modification was investigated in obese, diabetic Z

167 function (DD) through collagen deposition or titin modification.

168 shifts and titin phosphorylation, as well as titin modifications related to oxidative stress, in adju

169 es the native state of the human cardiac I27 titin module against unfolding without shifting its unfo

170 omic force microscopic screening of extended titin molecules revealed that the unfolded domains are d

171 iously characterized rat strain with altered titin mRNA splicing, we identified a loss-of-function mu

172 ed exon skipping between exons 50 and 219 of titin mRNA.

173 A novel A-band titin mutation, c.92167C>T (p.P30723S), was found in 1 p

174 en recent compelling evidence that highlight titin mutations as major determinants of human cardiomyo

175 Our findings indicate that titin mutations cause DCM by disrupting critical linkage

176 We provide an update on disease-associated titin mutations in cardiac and skeletal muscles and summ

177 und 3 factors explaining the distribution of Titin mutations: (1) alternative splicing, (2) whether t

178 to 35%, being peptides derived from nebulin, titin, myosin heavy chains, and troponin I proteins, tho

179 cle origin: including myofibrillar proteins (titin, myosin light chain 1/3, myomesin 3 and filamin-C)

180 s multiple myofibrillar substrates including titin, myosin-binding protein-C and cardiac troponin I (

181 ion was caused by hypophosphorylation of the titin N2-B unique sequence and hyperphosphorylation of t

182 We specifically identify titin N2B as a novel substrate of extracellular signal r

183 reducing the stiffer cardiac collagen I and titin n2b expression in the left ventricle of mice with

184 n of these molecular components in mediating titin N2B function remained unresolved.

185 entify Fhl1 as a novel negative regulator of titin N2B levels and phosphorylation-mediated mechanics.

186 ression/activity and phosphorylation at PEVK/titin N2B-unique sequence sites than nonfailing donor he

187 Phosphorylation at specific PEVK/titin N2B-unique sequence sites was decreased in DKO and

188 CaMKII also phosphorylated the cardiac titin N2B-unique sequence.

189 so propose a potential mechanism for a known titin-N2B cardiomyopathy-causing mutation that involves

190 Fhl1 directly interferes with Erk2-mediated titin-N2B phosphorylation.

191 We highlight the critical region in titin-N2B that interacts with Fhl1 and residues that are

192 there was no change in maximum force or the titin N2BA/N2B isoform ratio and there was no titin hapl

193 titins in the hearts, called supercompliant titin (N2BAsc), which, within 3 weeks after raloxifene i

194 Intact titin, nebulin and filamin were shown to break down duri

195 resent here the X-ray structure of the human titin:obscurin M10:O1 complex extending our previous wor

196 ocytes are consistent with the view that the titin:obscurin/Obsl1 complexes might be a platform for h

197 absent from the Z-disk and M-band regions of titin (P</=0.01 for all comparisons).

198 g reduced systemic blood pressure, increased titin phosphorylation and prevented cardiac hypertrophy

199 omyocytes in vivo, coinciding with increased titin phosphorylation and suppressed subclinical inflamm

200 , myocardial passive stiffness, collagen, or titin phosphorylation but had an increase in biomarkers

201 To distinguish cTnI from cMyBP-C/titin phosphorylation effects on the force-pCa relations

202 +/- 0.07 versus control, 0.91 +/- 0.08), but titin phosphorylation in RV tissue of PAH patients was s

203 Deranged CaMKII-dependent titin phosphorylation occurs in heart failure and contri

204 ent stiffness, insoluble collagen, increased titin phosphorylation on PEVK S11878(S26), reduced phosp

205 Titin phosphorylation was assessed in CaMKIIdelta/gamma

206 CaMKII-dependent site-specific titin phosphorylation was quantified in vivo by mass spe

207 All-titin phosphorylation was reduced by >50% in DKO but inc

208 bserved only in mild RV dysfunction, whereas titin phosphorylation was reduced in both mild and sever

209 s the importance of titin-isoform shifts and titin phosphorylation, as well as titin modifications re

210 pecific antibodies did not detect changes in titin phosphorylation.

211 Titin plays crucial roles in sarcomere organization and

212 at the tandem immunoglobulin (Ig) segment of titin plays in stiffness generation and whether shorteni

213 fide-bonded variant of the I91 human cardiac titin polyprotein.

214 t Rbm20 mediates exon skipping by binding to titin pre-mRNA to repress the splicing of some regions;

215 of Rbm20 protein on the partially processed titin pre-mRNAs.

216 he impact of protein-protein interactions on titin properties and functions.

217 Titin properties were analyzed in Langendorff-perfused m

218 Finally, we demonstrate that mutant titin protein in iPS cell-derived cardiomyocytes results

219 ions cause hereditary cardiomyopathy and how titin protein is mechanically active in skeletal and car

220 eactivity with an unrelated epitope from the Titin protein presented on cardiac tissue.

221 The titin protein was analyzed by Western blotting and TTN g

222 within the core of a single Ig domain of the titin protein.

223 Upregulating compliant titins reduces diastolic chamber stiffness owing to the

224 regions, but not the disordered PEVK domain (titin region rich in proline, glutamate, valine, and lys

225 Understanding mechanisms underlying titin regulation in cardiac muscle function is of critic

226 ng mutations in the giant sarcomeric protein Titin result in dilated cardiomyopathy and skeletal myop

227 from the A-band of the giant muscle protein titin, reveal that they form tightly associated domain a

228 in a mouse model in which we deleted two of titin's C-zone super-repeats, thick filament length is r

229 Titin's force is generated by its I-band region, which i

230 mutation weakens the structural integrity of titin's Ig10 domain and suggests an Ig domain disease me

231 Thus, our work supports titin's important roles in diastolic function and diseas

232 Due to titin's large size (363 coding exons), current web appli

233 used to study the thick filament length and titin's molecular elasticity.

234 ay from the Z disk, increasing the strain on titin's molecular spring elements.

235 This expands the spectrum of titin's roles in cardiomyopathies.

236 be dominated by greatly increased lengths of titin's spring elements.

237 f 20 (RBM20) regulates the contour length of titin's spring region and thereby determines the passive

238 he IA junction moves the attachment point of titin's spring region away from the Z disk, increasing t

239 A mutation in the tenth Ig-like domain of titin's spring region is associated with arrhythmogenic

240 novel mouse model with a genetically altered titin splicing factor; integrative approaches were used

241 Inhibition of the RNA binding motif-20-based titin splicing system upregulates compliant titins, whic

242 croarray analysis revealed no adaptations in titin splicing, whereas novel phospho-specific antibodie

243 Titin spring elements behaved predominantly as monomers

244 evealed increased extension of the remaining titin spring segments as the sole likely underlying mech

245 CaMKII phosphorylates the titin springs at conserved serines/threonines, thereby l

246 le and heart, both sHSPs associated with the titin springs, in contrast to the cytosolic/Z-disk local

247 line, glutamate, valine, and lysine), of the titin springs.

248 s in the loss of Hsp90 methylation, impaired titin stability, and altered muscle function.

249 tension after MI, suggesting that MI-induced titin stiffening is mediated by elevated levels of the c

250 ic heart failure and ponder the evidence for titin stiffness as a potential target for pharmacologica

251 ecent studies demonstrate unequivocally that titin stiffness increases upon muscle activation, but th

252 Findings suggest that titin stiffness is a principal regulator of the contract

253 Physiological or pathological changes to titin stiffness therefore affect contractility.

254 thin and thick filaments that correlate with titin strain and myofilament LDA.

255 ll, our results reveal a correlation between titin strain and the Frank-Starling mechanism.

256 To clarify the role of titin strain in LDA, we isolated myocardium from either

257 y source, and Ca(2+)-dependent stiffening of titin stretched during eccentric muscle contractions.

258 a web application, TITINdb, which integrates titin structure, variant, sequence and isoform informati

259 g olfactory receptors and the muscle protein titin), suggesting extensive false-positive findings tha

260 The titin-telethonin complex, essential for anchoring filame

261 s, we found that the mechanical stability of titin-telethonin is modulated primarily by the strength

262 omplex at the cardiac-specific N2B region of titin that includes four-and-a-half LIM domain protein-1

263 deranged post-translational modification of titin that results in increased passive myocardial stiff

264 Phylogenetic analyses suggest that titin, the largest known protein, first appeared in the

265 Titin, the largest protein known, forms a giant filament

266 o study the degradation of the giant protein titin throughout the dry-curing process (2, 3.5, 5, 6.5,

267 he mechanical anchoring of the giant protein titin to both the sarcomere M-band and the Z-disk.

268 th a special emphasis on the contribution of titin to diastolic stiffness.

269 of sallimus (Sls), also known as Drosophila titin, to observe sarcomere assembly during IFM developm

270 rom the RBM20-regulated I-band region of the titin transcript.

271 Titin-truncating variants (TTNtv) commonly cause dilated

272 Titin-truncating variants (TTNtvs) are the major cause o

273 nding of dilated cardiomyopathy (DCM) due to titin truncation (TTNtv) may help guide patient stratifi

274 We amassed Titin truncation mutation information from 1714 human di

275 cal model to explain the observed pattern of Titin truncation variants in patients with dilated cardi

276 ected dilated cardiomyopathy patients harbor Titin truncations in the C-terminal two-thirds of the pr

277 ology, we generated six zebrafish lines with Titin truncations in the N-terminal and C-terminal regio

278 led the likely causal genetic variant in the titin (TTN) gene (g.274375T>C; p.Cys30071Arg) within a s

279 In addition to titin (TTN), we identified a set of 30 genes with conser

280 that truncate the massive sarcomere protein titin [TTN-truncating variants (TTNtvs)] are the most co

281 tations in the sarcomeric structural protein titin (TTNtv).

282 rocesses 3 days after MI involve accelerated titin turnover by the ubiquitin-proteasome system.

283 A single interaction of alpha-actinin and titin turns out to be surprisingly weak if force is appl

284 Cardiac titin undergoes developmental size reduction from 3.7 me

285 , current web applications are unable to map titin variants to domain structures.

286 to facilitate the correct classification of titin variants.

287 In sarcomeres, sHSP binding to titin was actin filament independent and promoted by fac

288 The stiffness of A-band titin was found to be high, relative to that of I-band t

289 sition were similar between groups; however, titin was hyperphosphorylated in HFpEF and correlated wi

290 in the second immunoglobulin-like domain of titin, was introduced in a bacterially expressed recombi

291 leven sarcomere genes, CRYAB, alpha-GAL, and titin were screened.

292 In patients with DCM, TTNtv throughout titin were significantly associated with DCM.

293 Compliant titins were upregulated through deletion of the RNA Reco

294 the isoform switch of the sarcomeric protein titin, which adjusts ventricular filling.

295 eres are interconnected by the giant protein titin, which is a scaffolding filament, signaling platfo

296 iants situated in the I-, A-, and M-bands of titin, which is the largest protein in humans and respon

297 titin splicing system upregulates compliant titins, which improves diastolic function and exercise t

298 iac isoform of myosin-binding protein-C, and titin will aid in understanding of the structural effect

299 etch therefore results in movement of A-band titin with respect to the thick filament backbone, and t

300 Stable anchoring of titin within the muscle Z-disk is essential for preservi