ライフサイエンスコーパス: titin

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

2 xposed to mechanical forces, such as cardiac titin.

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

4 matrix fibrillar collagen and cardiomyocyte titin.

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

6 oth effects favor a more extensible state of titin.

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

8 mere formation in the absence of full-length titin.

9 trols expressing both full-length and Cronos titin.

10 disarray despite the presence of full-length titin.

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

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

13 domains further towards the C terminus along titin.

14 s were found in 178 patients (37%): 54 (11%) Titin; 19 (4%) Lamin A/C (LMNA); 24 (5%) structural cyto

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

16 largest gene in the human body, encodes TTN (titin), a protein that plays key structural, development

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

18 Titin, a sarcomeric protein expressed primarily in stria

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

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

21 effect of baseline phosphorylation and from titin aggregation.

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

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

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

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

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

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

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

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

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

31 that cause hypertrophic cardiomyopathy, the titin and sarcomere variants that cause dilated cardiomy

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

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

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

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

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

37 immunoblotting using phosphoserine-specific titin-antibodies.

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

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

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

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

42 The results strongly support the role of titin as a blueprint for the thick filament and the arra

43 nd tunability of the I-band spring implicate titin as a force contributor that, during contraction, a

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

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

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

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

48 on as a stiff elastic element in series with titin at the myotendinous junction.

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

50 pid cutting of elastic titin to quantify how titin-based forces define myocyte ultrastructure and mec

51 d increased expression of proteins linked to titin-based mechanotransduction (CryAB, ANKRD1, muscle L

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

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

54 e low titin levels in E2-KOs lead to reduced titin-based stiffness and increased strain on the remain

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

56 perties of titin; however, whether and where titin becomes oxidized in vivo is less certain.

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

58 TTN-Z(-/-)-CMs exclusively express Cronos titin, but these cells produce lower contractile force a

59 Using our system, we specifically sever titin by digestion with TEV protease, and find that the

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

61 f the muscle specific clock-controlled gene, Titin-cap (Tcap).

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

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

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

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

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

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

68 Here, we use a novel titin-cleavage (TC) mouse model that allows specific and

69 Strikingly, when titin-cleaved muscles contract, myosin-containing A-band

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

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

72 stress response is consistent with truncated titin contributing to the mechanical properties in M1/2-

73 pression of a recently discovered isoform of titin, Cronos, which initiates downstream of the truncat

74 To study titin deficiency versus dysfunction, the authors generat

75 The pathways that govern titin-dependent cardiac growth and contribute to disease

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

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

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

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

80 failing human myocardium because of reduced titin distensibility.

81 Cardiomyocytes were stretched to investigate titin distensibility.

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

83 At pulling forces < 10 pN, titin domains are recruited to the unfolded state, and p

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

85 esent data that allow us to precisely locate titin domains axially along the thick filament from its

86 This disposition also allows a subgroup of titin domains comprising two or three fibronectin domain

87 excursions inside telethonin and the pulled titin domains.

88 ed covalent tethering enables examination of titin dynamics under force using magnetic tweezers.

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

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

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

92 This establishes intact titin filaments as critical force-transmission networks,

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

94 S-glutathionylation and disulfide bonding of titin fragments could alter the elastic properties of ti

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

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

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

98 Truncating variants in the Titin gene (TTNtvs) are common in individuals with idiop

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

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

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

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

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

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

105 To date, the protein titin has been demonstrated as a major contributor to th

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

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

108 Titin holds promise as a therapeutic target for heart fa

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

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

111 gments could alter the elastic properties of titin; however, whether and where titin becomes oxidized

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

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

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

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

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

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

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

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

120 Promoting titin Ig unfolding in cardiomyocytes caused elevated sti

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

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

123 ature dependent unfolding and refolding of a titin immunoglobulin domain and alpha-actinin spectrin r

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

125 To investigate the function of titin in human CMs, we used CRISPR/Cas9 to generate homo

126 The truncated titin in M1/2-KO helps maintain the passive properties a

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

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

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

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

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

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

133 3-mediated cleavage of its in vivo substrate titin in tissue extracts.

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

135 20(DeltaRRM)-raloxifene mice expressed large titins in the hearts, called supercompliant titin (N2BAs

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

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

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

139 Titin is a giant elastic protein that spans the half-sar

140 Titin is a giant filamentous protein of the muscle sarco

141 Titin is a large filamentous protein that is responsible

142 The giant muscle protein titin is a major contributor to passive force; however,

143 The C-terminal portion of titin is closely associated with the thick, myosin-conta

144 We demonstrate that Cronos titin is expressed in developing human CMs and is able t

145 The giant protein titin is expressed in vertebrate striated muscle where i

146 Cronos titin is highly expressed in human fetal cardiac tissue,

147 The giant sarcomere protein titin is important in both heart health and disease.

148 Furthermore, Cronos titin is necessary for proper sarcomere function in huma

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

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

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

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

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

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

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

156 Titin isoform expression was evaluated with agarose gels

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

158 ion of cMyBP-C Ser282 but was independent of titin isoform shift.

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

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

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

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

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

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

165 arcomere stretch and the expression of stiff titin isoforms.

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

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

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

169 ac phenotypes differed considerably: loss of titin leads to dilated cardiomyopathy with combined syst

170 Progressive depletion of titin leads to sarcomere disassembly and atrophy in stri

171 mechanical properties in M1/2-KOs, while low titin levels in E2-KOs lead to reduced titin-based stiff

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

173 We conclude that a titin-like dynamic spring in the I-band, made by an unda

174 Titin may thereby provide complex safety mechanims for p

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

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

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

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

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

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

181 In the complete knockout, remaining titin molecules experience increased strain, resulting i

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

183 ffness and increased strain on the remaining titin molecules.

184 To perform this function, elastic titin must change stiffness or extensible length, unveil

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

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

187 ribute to the molecular understanding of why titin mutations differentially affect cardiac growth and

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

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

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

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

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

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

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

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

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

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

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

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

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

201 UnDOx also enhances titin phosphorylation and, importantly, promotes noncons

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

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

204 Titin phosphorylation was assessed in CaMKIIdelta/gamma

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

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

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

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

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

210 Titin properties were analyzed in Langendorff-perfused m

211 h progressive postnatal loss of the complete titin protein by removing exon 2 (E2-KO) or an M-band tr

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

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

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

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

216 e state-of-the-art on large compounds (e.g., Titin protein) and on compounds whose elements have many

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

218 in line with the PEVK and Ig-like repeats of titin rather than those reported for repeats in spectrin

219 Upregulating compliant titins reduces diastolic chamber stiffness owing to the

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

221 rders of magnitude larger than expected from titin-related passive force.

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

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

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

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

226 ges requires mechanical transduction through titin's intact polypeptide chain.

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

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

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

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

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

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

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

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

235 sin binding protein-C are not related to the titin sequence previously assumed; rather, they relate t

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

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

238 Titin spring elements behaved predominantly as monomers

239 bulin domains preferentially from the distal titin spring region become oxidized in vivo through the

240 led homotypic interactions within the distal titin spring to stabilize this segment and regulate myoc

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

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

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

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

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

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

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

248 However, current estimates of titin stiffness, deduced from the passive force-SL relat

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

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

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

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

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

254 The titin-telethonin complex, essential for anchoring filame

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

256 to mutations or site-directed mutagenesis in titin that alter the I-band stiffness.

257 likely prevented by the cytoskeletal protein titin that connects the thick filament with the sarcomer

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

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

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

261 rying a HaloTag-TEV insertion in the protein titin, the main determinant of myocyte stiffness.

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

263 diastolic dysfunction-the absence of M-band titin to cardiac atrophy and preserved function.

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

265 allows specific and rapid cutting of elastic titin to quantify how titin-based forces define myocyte

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

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

268 Titin-truncating variants (TTNtv) are the most common ge

269 Titin-truncating variants (TTNtv) commonly cause dilated

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

271 Titin-truncating variants (TTNtvs) predominated, occurri

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

273 We amassed Titin truncation mutation information from 1714 human di

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

275 ting a role in the differential pathology of titin truncation versus deficiency of the full-length pr

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 Mutations in the gene encoding for titin (TTN) are the leading known cause of familial dila

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

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

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

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

283 Via oxidation type-specific modification of titin, UnDOx modulates human cardiomyocyte passive force

284 Background Truncating titin variants (TTNtv) are the most prevalent genetic ca

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

292 Compliant titins were upregulated through deletion of the RNA Reco

293 ve modifications to the giant muscle protein titin, which in turn can determine the progression of he

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

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

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

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

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

299 Interactions of elastic titin with sarcomeric actin filaments are revealed.

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