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Query: UNIPROT:P06889 (Mol)
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The function of the high molecular weight structural proteins from muscle, namely vertebrate titin, arthropod projectin and nematode twitchin, remains to be established. Using a simple method for the purification of projectin from crayfish and Drosophila melanogaster, a polyclonal antibody has been raised against crayfish projectin, and shown to immunocrossreact with Drosophila projectin but not with rat titin. In this study, evidence is presented that projectin and twitchin may share functional protein kinase domains, indicating a possible relationship between them. Projectin has a serine/threonine protein kinase activity. This supports the relationship with twitchin since, in sequence analysis of the latter, a protein-kinase-like domain has been found. Moreover, projectin is capable of autophosphorylation in vitro. These kinase activities imply regulatory functions for this group of proteins, extending its previously assumed structural role in the sarcomere. We also show here that projectin is phosphorylated in vivo at serine residues, as described for titin.
J Mol Biol 1992 Mar 20
PMID:Autophosphorylating protein kinase activity in titin-like arthropod projectin. 156 Apr 53

The protein titin has been localized by electron microscopy of myofibrils labelled with monoclonal antibodies. The data are consistent with individual titin molecules extending from near the M-line to beyond the ends of thick filaments, a distance of approximately 1 micron. In the A-band, titin appears to be bound to thick filaments, probably to the outside of the filament shaft. Molecules of titin in this configuration provided an obvious mechanism by which the length of thick filaments could be regulated accurately.
J Mol Biol 1989 Jan 05
PMID:Does titin regulate the length of muscle thick filaments? 292 7

A new thick-filament-associated protein, the 86 kd protein, of chicken pectoralis major muscle was isolated from a crude C-protein preparation by a method similar to that used to purify H-protein from rabbit skeletal muscle. However, the protein with an apparent Mr of 86,000 and 370,000 as estimated by gel electrophoresis and gel permeation, respectively, is not related to C-protein and differs from rabbit H-protein by its elution behaviour from hydroxyapatite columns, by its molecular weight, ultraviolet light spectrum, amino acid composition and localization, and by its amount present in myofibrils. The amino acid composition reveals a high content of proline and gel permeation indicates an either highly asymmetric or polymeric structure of the molecule. Antibodies raised in rabbits against the 86 kd protein were demonstrated by double immunodiffusion and immunoblotting experiments to be specific for this protein. They show no cross-reactivity with any other myofibrillar protein of chicken pectoralis muscle, e.g. myosin, M-band proteins, titin or C-protein, nor did they exhibit a significant cross-reactivity with H-protein from rabbit. The 86 kd protein, which has been purified also by antibody affinity chromatography from a freshly prepared Guba-Straub extract of washed myofibrils, is a specific myofibrillar component located within each half of the A-band.
J Mol Biol 1985 Nov 20
PMID:Novel thick filament protein of chicken pectoralis muscle: the 86 kd protein. I. Purification and characterization. 393 33

A procedure has been developed for the extraction and purification of the massive myofibrillar protein titin without exposing it to denaturing conditions. The form of the molecule that has been isolated is soluble at high ionic strength and alkaline pH, but precipitates in low salt or at pH values below 7. Sedimentation velocity experiments indicate that titin is a highly asymmetric molecule with a sedimentation coefficient of 13.4 S. This asymmetry is confirmed by electron microscopy of rotary-shadowed specimens, which shows string-like structures of diameter 40 A and lengths up to 8000 A. Significant differences were observed depending on whether the electron microscope specimens were prepared by spraying or by layering of the titin onto a mica substrate; we tentatively attribute these differences to elasticity in the titin, revealed by the high shearing forces that accompany spraying. In accord with this, the circular dichroism spectrum of titin indicates that its secondary structure is largely random coil, a conformation characteristic of elastic proteins such as elastin. Negative staining of titin again shows long string-like structures, but these can now be seen to have an appearance similar to a string of beads, where the spacing between successive beads is about 40 A. Very similar beaded strings have been observed also associated with negatively stained separated native thick filaments; these are found running alongside the cross-bridge regions and in coils near the filament ends. Since the periodicity of the strings is similar to that of end-filaments, recently identified structures at the tips of thick filaments, it is likely that end-filaments are formed from titin. Titin comprises approximately 9% of the myofibrillar mass, which means that it is the third most abundant protein in muscle. The possible role of titin in forming elastic filaments within myofibrils is discussed.
J Mol Biol 1984 Dec 05
PMID:Purification and properties of native titin. 651 59

Cardiomyocytes of chronic hibernating myocardium are affected by partial to complete loss of sarcomeres, accumulation of glycogen, adaptations in size and shape of mitochondria, reorganisation of nuclear chromatin and depletion of sarcoplasmic reticulum. The nature of these changes, which from a purely morphologic viewpoint are akin to dedifferentiation, needed further clarification at the molecular level. For this purpose we have studied the expression and reorganization of titin, one of the earliest markers of cardiomyocytes differentiation. By use of monoclonal antibodies, recognizing different epitopes distributed over the whole length of the titin molecule, we were able to detect changes in its molecular organization as a result of chronic hibernation. The epitopes of the titin molecule attached to the Z-disc and those present close to the M-line remained detectable at all stages of hibernation, while epitopes at the A-I junction and parts of the myosin anchoring region of the molecule became masked or were lost. A fragmented or punctuated appearance of the titin staining pattern with antibodies to A-I junction related epitopes is found in cells which we consider to represent a more advanced stage of dedifferentiation. Changes in the distribution of the titin molecule or its molecular environment in hibernating myocardium resemble at least in part changes occurring during muscle cell differentiation, although in reversed order.
J Mol Cell Cardiol 1995 May
PMID:Molecular changes of titin in left ventricular dysfunction as a result of chronic hibernation. 747 78

Cross-striated muscle contains an elastic cytoskeleton comprised of the giant protein titin and several associated proteins. cDNA sequencing revealed that all these proteins are immunoglobulin superfamily members. This modular structure opens the possibility to dissect the proteins involved into functional units and to approach the problem of structure-function correlation at the molecular level.
J Mol Cell Cardiol 1995 Apr
PMID:The anatomy of a molecular giant: how the sarcomere cytoskeleton is assembled from immunoglobulin superfamily molecules. 756 7

Immunocytochemical investigation was performed on the cytoskeletal proteins in cardiac tissue of the cardiomyopathic hamster. Male cardiomyopathic UM-X7.1 hamsters at 180 days of age (n = 8) and age- and sex-matched normal BIO-RB hamsters (n = 8) were used in this study. Immunofluorescence microscopy using monoclonal antibodies against desmin, alpha-actinin, titin, and vincullin was employed. The heart weight to body weight ratio was significantly increased in the heart of cardiomyopathic hamster compared with that of normal hamster. In cardiomyopathic hamster, the left ventricular cavity was markedly dilated. Light microscopically, hypertrophy and atrophy of myocytes and myocardial fibrosis were prominently observed in cardiomyopathic myocardium. Immunocytochemically, desmin, alpha-actinin and titin showed the cross striations along the myofibers in normal myocardium. In contrast, in cardiomyopathic myocardium, desmin was irregularly distributed in myocytes and the amount of desmin was increased. Loss of cross striations of alpha-actinin and titin were frequently observed. Immunofluorescence against vinculin was not significantly altered. We conclude that the alterations of cytoskeletal proteins in myocardial cells may relate to decreased myocardial function in cardiomyopathic hamster failing heart.
Mol Cell Biochem 1995 Mar 09
PMID:Pathological changes of myocardial cytoskeleton in cardiomyopathic hamster. 779 49

Our own previous ultrastructural studies in human hearts with dilated cardiomyopathy and heart failure showed sarcomeric and cytoskeletal disarrangement. On the basis of these findings we tested the hypothesis that in cardiomyopathic failing hearts not only the sarcomere structure but also the organization and the amount of numerous contractile proteins are disturbed. Titin was included in this study because it is the elastic "third" filament of the sarcomere and also plays an important role as template for myosin and actin filaments in sarcomerogenesis. Human cardiac tissue obtained at the time of transplantation surgery was investigated using immunohistochemistry with monoclonal antibodies against titin, myosin, actin, tropomyosin, and troponin T. Additionally, isolated myocytes from rat or pig heart were used for the standardization of the localization pattern. In normal tissue, myosin and the thin filament complex showed a regular cross striation that was wider in myosin staining than for actin, troponin T, and tropomyosin corresponding with the different width of the A and I bands in the sarcomere. Titin localization in normal human and animal myocardium showed a regular cross striation pattern. In diseased cardiac tissue titin fluorescence intensity was reduced and frequently disorganization or almost complete loss of titin from many myocytes were present. Severe abnormalities of contractile proteins consisting of disarrangement or lack of filaments were also observed. Double staining procedures showed that in the same myocyte defects of the contractile apparatus were accompanied by a simultaneous reduction of titin indicating that the "third" sarcomeric filament system is involved in heart failure. Abnormalities of titin expression may be especially important because titin significantly influences sarcomeric elastic behaviour and is necessary as template for the organization of newly synthesized myosin and actin filaments. The loss of titin may contribute to the altered compliance in failing hearts. It is concluded that disorganization and loss of titin, myosin, and the thin filament complex are severe in the failing human heart because of dilated cardiomyopathy and that these changes may represent several of the most important components of the structural correlate of reduced cardiac function.
J Mol Cell Cardiol 1994 Oct
PMID:Altered expression of titin and contractile proteins in failing human myocardium. 786 90

Titin and twitchin are giant proteins expressed in muscle. They are mainly composed of domains belonging to the fibronectin class III and immunoglobulin c2 families, repeated many times. In addition, both proteins have a protein kinase domain near the C-terminus. This paper explores the evolution of these and related muscle proteins in an attempt to determine the order of events that gave rise to the different repeat patterns and the order of appearance of the proteins. Despite their great similarity at the level of sequence organization, titin and twitchin diverged from each other at least as early as the divergence between vertebrates and nematodes. Most of the repeating units in titin and twitchin were estimated to derive from three original domains. Chicken smooth-muscle myosin light-chain kinase (smMLCK) also has a kinase domain, several immunoglobulin domains, and a fibronectin domain. From a comparison of the kinase domains, titin is predicted to have appeared first during the evolution of the family, followed by twitchin and with the vertebrate MLCKs last to appear. The so-called C-protein from chicken is also a member of this family but has no kinase domain. Its origin remains unclear but it most probably pre-dates the titin/twitchin duplication.
J Mol Evol 1994 Apr
PMID:The evolution of titin and related giant muscle proteins. 800 7

We investigated relative amounts of titin, myosin light chains (MLC), C-protein, and myosin heavy chains (MHC) in the functionally intact contractile apparatus of embryonic, adult normal, and adult failing human left ventricle by SDS polyacrylamide gel electrophoresis and Western blot analysis. The amount of titin and the titin-MHC ratio was significantly (P < 0.05) lower in the embryonic and adult failing human compared to the adult normal fibres. Additionally, we found a protein band having a lower molecular weight but the same immunoreactivity as native titin (fast-migrating titin; FM-titin) in the failing heart only. The MLC-1/MLC-2 ratio was about 1.0 in normal and failing hearts but about 2.0 in the embryonic heart. Relative amount of C-protein was the same in normal and failing fibres but lower in the embryonic ventricles. Length-tension ratio of chemically skinned fibres prepared from terminally failing hearts was impaired compared to normal heart fibres. We conclude that both the reduced titin/MHC ratio and the expression of a structurally different titin form may be involved in the impaired contractile function of the terminally failing human heart.
J Mol Cell Cardiol 1994 Mar
PMID:Titin, myosin light chains and C-protein in the developing and failing human heart. 802 19


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