Structure and function of titin and nebulin

Keller, Thomas C. S.

doi:10.1016/0955-0674(95)80042-5

Cited by 63 publications

(34 citation statements)

References 64 publications

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“…Titin is a 300-kDa cytoskeletal protein that spans in a spring-like fashion from the Z disc to the M band and, under normal conditions, ensures elasticity and extensibility of the sarcomere [16]. In the present study, a decrease in the expression of total titin and the compliant N2BA titin isoform and an increase in the expression of the stiff N2B titin isoform was observed in the LV of untreated HF dogs that was normalized by chronic CCM therapy.…”

Section: Discussionmentioning

confidence: 55%

Effects of Chronic Therapy with Cardiac Contractility Modulation Electrical Signals on Cytoskeletal Proteins and Matrix Metalloproteinases in Dogs with Heart Failure

Rastogi¹,

Mishra²,

Zacà³

et al. 2007

Cardiology

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Objectives: Therapy with cardiac contractility modulation (CCM) electrical signals delivered to left ventricular (LV) muscle during the absolute refractory period improves LV systolic and diastolic function in dogs with heart failure (HF). This study examined the effects of CCM therapy on mRNA and protein expression of cytoskeletal proteins, matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) in the LV myocardium of dogs with HF. Methods: HF was produced in 14 dogs by coronary microembolizations. Dogs were randomized to 3 months of CCM therapy (n = 7) or to sham-operated controls (n = 7). LV tissue from 6 normal (NL) dogs was used for comparison. mRNA expression was measured using reverse-transcriptase polymerase chain reaction and protein expression using Western blots. Results: Compared with NL dogs, controls showed upregulation of mRNA and protein expression of the cytoskeletal proteins tubulin and fibronectin and MMP-1, MMP-2 and MMP-9, and downregulation of the cytoskeletal protein titin. Normalized expression of all these genes and proteins was seen after CCM therapy. No differences in expression of TIMP-1 and TIMP-2 were observed among groups. Conclusions: CCM therapy normalizes expression of key cytoskeletal proteins and MMPs and may partly explain the improvement in LV function seen in HF following CCM therapy.

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Section: Discussionmentioning

confidence: 55%

Effects of Chronic Therapy with Cardiac Contractility Modulation Electrical Signals on Cytoskeletal Proteins and Matrix Metalloproteinases in Dogs with Heart Failure

Rastogi¹,

Mishra²,

Zacà³

et al. 2007

Cardiology

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“…6 pM for ML-7 and ~3 . 4 pM for ML-9 of TWK-39 (data not shown). This indicates a very similar sensitivity of TWK-39 to ML-9 as previously determined for MLCK from smooth-muscle and nonmuscle cells ( K , = 3.8-4.1 pM; [IS]), in contrast to a K, value of 49 pM for skeletal muscle MLCK [18], while the ML-7 sensitivity of the twitchin kinases is much lower than that of smoothmuscle MLCK (K, = 0.3 pM [18]).…”

Section: Resultsmentioning

confidence: 99%

Substrate Specificity and Inhibitor Sensitivity of Ca²⁺/S100‐dependent Twitchin Kinases

Heierhorst¹,

Tang²,

Lei³

et al. 1996

European Journal of Biochemistry

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Myosin-associated giant protein kinases of the titinkwitchin-like superfamily have previously been implicated in the regulation of muscle function, based on genetic and physiological studies. We find that recombinant constitutively active Caenorhabditis eleguris and Aplysiu twitchin kinase fragments differ in their catalytic activities and peptide-substrate specificities, as well as in their sensitivities to the naphthalene sulfonamide inhibitors 1-(5-chloronaphthalenesulfonyl)-1H-hexahydro-l,4-diazepine (ML-7) and 1-(5-iodonaphthalenesulfonyl)-1H-hexahydro-l,4-diazepine (ML-9). The constitutively active Aplysia twitchin kinase fragment has a remarkably high activity (V,,,,, > 100 pmol . min-' . mg-') towards some substrate peptides. The autoinhibited forms of these twitchin kinases can be activated in a Ca"-dependent manner by the dimeric form of the SlOOAl protein (S100A1,). The twitchin kinase SIOOAI,-binding site can also bind Ca' +/calmodulin but neither kinase is activated by calmodulin. The data provide a functional basis for the ongoing crystallographic study of twitchin kinase fragments.Keywords: protein kinase; twitchin; titin ; S100; calmodulin.The myosin-associated giant proteins such as titin, twitchin and projectin are predominantly composed of repeating modular fibronectin-type-Ill-like and immunoglobulin-like domains [I -31. These domains are considered to be important for the cytoskeletal functions of these proteins as possible molecular rulers for the length and elasticity of the sarcomere 141. Titinltwitchinlike proteins also contain a single protein kinase domain [1-31, and mutant phenotypes of Caenorhubditis elegans twitchin [ 11 and Drosophila projectin [3] indicate that the kinase may be involved in the regulation of myosin activity.The twitchin kinase domain is distantly related to myosin light chain kinases (MLCKs) [ 11. Constitutively active recombinant twitchin kinases phosphorylate a MLCK substrate peptide [5, 61, and Aplysia regulatory myosin regulatory light chains (MLCs) have been identified as the first endogenous substrates for any of the giant protein kinases [6]. C. e1egun.s and Aplysia twitchin kinases contain an autoinhibitory region just C-terminal to the catalytic core 1.5581 similar to that of calmodulin-regulated kinases. Crystal structures of these kinases demonstrate that this region inhibits the kinase by an intrasteric mechanism

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“…The longest isoforms span the *1 lm length across one-half of the sarcomere (for reviews of titin see [Keller, III, 1995;Labeit and Kolmerer, 1995;Tskhovrebova and Trinick, 2003]. The N-terminus of each of these titin molecules is anchored in the sarcomere Z-disk through interaction with telethonin/ Tcap [Gregorio et al, 1998;Zou et al, 2006] and with a-actinin ].…”

Section: Introductionmentioning

confidence: 99%

Molecular identification and localization of cellular titin, a novel titin isoform in the fibroblast stress fiber

Cavnar

Olenych

Keller

2007

Cell Motil. Cytoskeleton

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We previously discovered a large titin-like protein-c-titin-in chicken epithelial brush border and human blood platelet extracts that binds alpha-actinin and organizes arrays of myosin II bipolar filaments in vitro. RT-PCR analysis of total RNA from human megakaryoblastic (CHRF-288-11) and mouse fibroblast (3T3) nonmuscle cells reveal sequences identical to known titin gene exon sequences that encode parts of the Z-line, I-band, PEVK domain, A-band, and M-line regions of striated muscle titins. In the nonmuscle cells, these sequences are differentially spliced in patterns not reported for any striated muscle titin isoform. Rabbit polyclonal antibodies raised against expressed protein fragments encoded by the Z-repeat and kinase domain regions react with the c-titin band in Western blot analysis of platelet extracts and immunoprecipitate c-titin in whole platelet extracts. Immunofluorescent localization demonstrates that the majority of the c-titin colocalizes with alpha-actinin and actin in 3T3 and Indian Muntjac deer skin fibroblast stress fibers. Our results suggest that differential expression of titin gene exons in nonmuscle cells yields multiple novel isoforms of the protein c-titin that are associated with the actin stress fiber structures.

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Structure and function of titin and nebulin

Cited by 63 publications

References 64 publications

Effects of Chronic Therapy with Cardiac Contractility Modulation Electrical Signals on Cytoskeletal Proteins and Matrix Metalloproteinases in Dogs with Heart Failure

Effects of Chronic Therapy with Cardiac Contractility Modulation Electrical Signals on Cytoskeletal Proteins and Matrix Metalloproteinases in Dogs with Heart Failure

Substrate Specificity and Inhibitor Sensitivity of Ca²⁺/S100‐dependent Twitchin Kinases

Molecular identification and localization of cellular titin, a novel titin isoform in the fibroblast stress fiber

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Structure and function of titin and nebulin

Cited by 63 publications

References 64 publications

Effects of Chronic Therapy with Cardiac Contractility Modulation Electrical Signals on Cytoskeletal Proteins and Matrix Metalloproteinases in Dogs with Heart Failure

Effects of Chronic Therapy with Cardiac Contractility Modulation Electrical Signals on Cytoskeletal Proteins and Matrix Metalloproteinases in Dogs with Heart Failure

Substrate Specificity and Inhibitor Sensitivity of Ca2+/S100‐dependent Twitchin Kinases

Molecular identification and localization of cellular titin, a novel titin isoform in the fibroblast stress fiber

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Substrate Specificity and Inhibitor Sensitivity of Ca²⁺/S100‐dependent Twitchin Kinases