Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chaen et al. (1986. J. Biol. Chem. 261:13632-13636) showed that treatment of relaxed single muscle fibers with para-phenylenedimaleimide (pPDM) results in inhibition of a fiber's ability to generate active force and a diminished ATPase activity. They postulated that the inhibition of force production was due to pPDM's ability to prevent crossbridges from participating in the normal ATP hydrolysis cycle. We find that the crossbridges produced by pPDM treatment of relaxed muscle cannot bind strongly to the actin filaments in rigor, but do bind weakly to the actin filaments in the presence and also absence of ATP. After pPDM treatment, fiber stiffness, as measured using ramp stretches of varying duration, is ATP-insensitive and identical to that of untreated relaxed fibers (both at high [165 mM] and low [40 mM] ionic strength). These results suggest that the pPDM-treated crossbridges, in both the presence and absence of ATP, are locked in a state that resembles the weakly-binding myosin ATP state of normal crossbridges. Their resemblance to the ATP-crossbridges of relaxed untreated fibers is quite strong; both bind to actin about equally tightly and have similar attachment and detachment rate constants. We also found that crossbridges are locked in a weakly-binding state after treatment with N-phenylmaleimide (NPM). In muscle fibers, this method of producing weakly-binding crossbridges appears preferable to pPDM treatment because, unlike treatment with pPDM, it does not increase the fiber's resting tension and stiffness and it does not disrupt the titin band seen on SDS-PAGE.
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PMID:Formation of ATP-insensitive weakly-binding crossbridges in single rabbit psoas fibers by treatment with phenylmaleimide or para-phenylenedimaleimide. 154 25

The insect muscle protein projectin (900 kDa) belongs to a novel family of cytoskeleton-associated protein kinases (titin, twitchin, and projectin) that are members of the immunoglobulin superfamily. The functions of these kinases are still unknown although recent data suggest a role in modulating muscle activity and generating passive elasticity. An important question is what are the in vivo substrates for these enzymes. We found a thin filament-associated 30 kDa protein that acts as an in vitro substrate for projectin kinase from Locusta migratoria. However, we did not find activators for projectin kinase. Neither calcium, calcium with calmodulin, nor cAMP activated the in vitro activity of projectin kinase. Binding studies revealed a strong interaction between projectin and thin filaments comparable with that of the projectin-myosin interaction. That an interaction might be possible in vivo is suggested by immunological studies showing that projectin is attached to the surface of myosin filaments. Since the molecular weights indicate that the 30 kDa protein might be troponin I, which is known to play a central role in modulating cardiac contractile activity, we studied whether phosphorylation of this protein by projectin changes the calcium sensitivity of the actomyosin ATPase. We found a significant increase in the calcium sensitivity. Thus, our results indicate the existence of a novel mechanism of regulation of muscle activity by a cytoskeleton-associated kinase.
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PMID:Projectin-thin filament interactions and modulation of the sensitivity of the actomyosin ATPase to calcium by projectin kinase. 967 13

By affinity chromatography utilizing alpha-cobrotoxin from digitonin-solubilized fractions of rabbit skeletal muscle, we found that many proteins are associated with the nicotinic acetylcholine receptor (AChR). In addition to the proteins we previously reported to bind to AChR (including dystrophin-dystrophin-associated protein (DAP) complex, utrophin, rapsyn, and actin; Mitsui et al. [1996] Biochem. Biophys. Res. Commun.224:802-807), alpha-actinin, desmin, myosin, tropomyosin, troponin T, and titin are also identified to be associated with AChR. Alkaline treatment or Triton X-100 solubilization released dystrophin-DAP complex, utrophin, and rapsyn from the AChR fraction, while actin and desmin remained associated. These findings demonstrate that AChR is supported primarily by a submembranous organization of actin and desmin filaments, and is linked to sarcomeric proteins via these filaments. To further investigate whether the association has any functional role, we studied the effect of acetylcoline on ATPase activity of the AChR fraction. Acetylcholine (0.5-4 microM) significantly activated Mg(2+)-ATPase activity of digitonin-solubilized AChR fraction (P < 0.05). Furthermore, we found that desmin as well as actin activated myosin Mg(2+)-ATPase activity. From these findings, it is suggested that desmin and actin form a submembranous organization in the postsynaptic region, and function as mediators of excitation of AChR to the sarcomeric contraction system.
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PMID:Functional association between nicotinic acetylcholine receptor and sarcomeric proteins via actin and desmin filaments. 1077 14

To elucidate the role of titin in the onset and development of dilated cardiomyopathy, the structure and functional properties of this protein from pathological myocardium (human left ventricle) were studied. By the use of SDS gel electrophoresis, a decrease in molecular weight of titin in dilated cardiomyopathy compared with norm (pig left ventricle) was revealed. The decrease correlated with the stage of the disease. A decrease in the length of molecules of pathological forms of titin was also found by electron microscopy, which confirms the results of electrophoresis tests. It was shown that, unlike titin from healthy muscle, pathological forms of titin do not activate but inhibit the main functional properties of control myosin: the actin-activated ATPase activity and its Ca2+ sensitivity. The direction of the changes in structure and functional properties of titin allows one to conclude about its contribution to the development of the pathology studied.
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PMID:[Changes in structure and functional properties of cytoskeletal elastic protein titin in dilated cardiomyopathy]. 1229 11

The influence of phosphorylation in vitro of the sarcomere cytoskeletal proteins titin and X-protein of skeletal muscles as well as C-protein of cardiac muscle of ground squirrel Citellus undulatus on the actin-activated ATPase activity of myosin and its Ca2+ sensitivity was studied. It was shown that phosphorylation lowers the activating effect of titin and C-protein and increases the inhibitory effect of X-protein on the enzymatic properties of actomyosin. The phosphorylation of the proteins has the most pronounced influence on Ca2+ sensitivity of actomyosin: it drops to a greater extent in the presence of phosphorylated C-protein and titin and is completely inhibited by phosphorylated X-protein. The inhibitory influence of phosphorylation in vitro of sarcomere cytoskeletal proteins on the above functional properties of the actomyosin system as well as the increase in the extent of phosphorylation of titin in vivo upon hibernation allow one to conclude that this posttranslation modification contributes to adaptive mechanisms of suppression of the contractile ability of muscles in this period.
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PMID:[Phosphorylation of sarcomeric cytoskeletal proteins--an adaptive factor for inhibiting the contractile activity of muscle during hibernation]. 1281 60

Myosin binding protein-C (MyBP-C) is a thick filament-associated protein localized to the crossbridge-containing C zones of striated muscle sarcomeres. The cardiac isoform is composed of eight immunoglobulin I-like domains and three fibronectin 3-like domains and is known to be a physiological substrate of cAMP-dependent protein kinase. MyBP-C contributes to thick filament structure via interactions at its C-terminus with the light meromyosin section of the myosin rod and with titin. The protein also has a role in the regulation of contraction, due to the binding of its N-terminus to the subfragment-2 portion of myosin, which reduces actomyosin ATPase activity; phosphorylation abolishes this interaction, resulting in release of the "brake" on crossbridge cycling. Several structural models of the interaction of MyBP-C with myosin have been proposed, although its precise arrangement on the thick filament remains to be elucidated. Mutations in the gene encoding cardiac MyBP-C are a common cause of hypertrophic cardiomyopathy, and this has led to increased interest in the protein's function. Investigation of disease-causing mutations in domains with unknown function has led to further insights into the mechanism of cMyBP-C action. This Review aims to collate the published data on those aspects of MyBP-C that are well characterized and to consider new and emerging data that further define its structural and regulatory roles and its arrangement in the sarcomere. We also speculate on the mechanisms by which hypertrophic cardiomyopathy-causing truncation and missense mutations affect the normal functioning of the sarcomere.
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PMID:Cardiac myosin binding protein C: its role in physiology and disease. 1516 15

Titin is known to interact with actin thin filaments within the I-band region of striated muscle sarcomeres. In this study, we have used a titin fragment of 800 kDa (T800) purified from striated skeletal muscle to measure the effect of this interaction on the functional properties of the actin-myosin complex. MALDI-TOF MS revealed that T800 contains the entire titin PEVK (Pro, Glu, Val, Lys-rich) domain. In the presence of tropomyosin-troponin, T800 increased the sliding velocity (both average and maximum values) of actin filaments on heavy-meromyosin (HMM)-coated surfaces and dramatically decreased the number of stationary filaments. These results were correlated with a 30% reduction in actin-activated HMM ATPase activity and with an inhibition of HMM binding to actin N-terminal residues as shown by chemical cross-linking. At the same time, T800 did not affect the efficiency of the Ca(2+)-controlled on/off switch, nor did it alter the overall binding energetics of HMM to actin, as revealed by cosedimentation experiments. These data are consistent with a competitive effect of PEVK domain-containing T800 on the electrostatic contacts at the actin-HMM interface. They also suggest that titin may participate in the regulation of the active tension generated by the actin-myosin complex.
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PMID:Regulation of the actin-myosin interaction by titin. 1556 Jul 99

We have cloned two new triadin isoforms from rat skeletal muscle, Trisk 49 and Trisk 32, which were named according to their theoretical molecular masses (49 and 32 kDa, respectively). Specific antibodies directed against each protein were produced to characterize both new triadins. Both are expressed in adult rat skeletal muscle, and their expression in slow twitch muscle is lower than that in fast twitch muscle. Using double immunofluorescent labeling, the localization of these two triadins was studied in comparison to well-characterized proteins such as ryanodine receptor, calsequestrin, desmin, Ca(2+)-ATPase, and titin. None of these two triadins are localized within the rat skeletal muscle triad. Both are instead found in different parts of the longitudinal sarcoplasmic reticulum. We attempted to identify partners for each isoform: neither is associated with ryanodine receptor; Trisk 49 could be associated with titin or another sarcomeric protein; and Trisk 32 could be associated with IP(3) receptor. These results open further fields of research concerning the functions of these two proteins; in particular, they could be involved in the set up and maintenance of a precise sarcoplasmic reticulum structure.
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PMID:Triadins are not triad-specific proteins: two new skeletal muscle triadins possibly involved in the architecture of sarcoplasmic reticulum. 1592 57

The active and passive contractile performance of skeletal muscle fibers largely depends on the myosin heavy chain (MHC) isoform and the stiffness of the titin spring, respectively. Open questions concern the relationship between titin-based stiffness and active contractile parameters, and titin's importance for total passive muscle stiffness. Here, a large set of adult rabbit muscles (n = 37) was studied for titin size diversity, passive mechanical properties, and possible correlations with the fiber/MHC composition. Titin isoform analyses showed sizes between approximately 3300 and 3700 kD; 31 muscles contained a single isoform, six muscles coexpressed two isoforms, including the psoas, where individual fibers expressed similar isoform ratios of 30:70 (3.4:3.3 MD). Gel electrophoresis and Western blotting of two other giant muscle proteins, nebulin and obscurin, demonstrated muscle type-dependent size differences of < or =70 kD. Single fiber and single myofibril mechanics performed on a subset of muscles showed inverse relationships between titin size and titin-borne tension. Force measurements on muscle strips suggested that titin-based stiffness is not correlated with total passive stiffness, which is largely determined also by extramyofibrillar structures, particularly collagen. Some muscles have low titin-based stiffness but high total passive stiffness, whereas the opposite is true for other muscles. Plots of titin size versus percentage of fiber type or MHC isoform (I-IIB-IIA-IID) determined by myofibrillar ATPase staining and gel electrophoresis revealed modest correlations with the type I fiber and MHC-I proportions. No relationships were found with the proportions of the different type II fiber/MHC-II subtypes. Titin-based stiffness decreased with the slow fiber/MHC percentage, whereas neither extramyofibrillar nor total passive stiffness depended on the fiber/MHC composition. In conclusion, a low correlation exists between the active and passive mechanical properties of skeletal muscle fibers. Slow muscles usually express long titin(s), predominantly fast muscles can express either short or long titin(s), giving rise to low titin-based stiffness in slow muscles and highly variable stiffness in fast muscles. Titin contributes substantially to total passive stiffness, but this contribution varies greatly among muscles.
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PMID:Isoform diversity of giant proteins in relation to passive and active contractile properties of rabbit skeletal muscles. 1623 Apr 67

We investigated the effects of repeated eccentric exercise for rat medial gastrocnemius muscle on ankle joint stiffness and muscle connectin (titin) isoform composition (longer form, alpha-connectin; shorter form, beta-connectin). Male Wistar rats were trained on a custom-made, isokinetic dynamometer (eccentric-exercise group, n = 6; sham-operated group, n = 6). The exercise session consisted of 20 eccentric contractions elicited by submaximal electric stimulations under anesthesia. The contracting muscle was forcibly lengthened by an isokinetic dorsi-flexion of the ankle joint (velocity, 30 degrees/s; range of motion, 45 degrees). Rats in the eccentric-exercise group were trained every two days for 20 days (10 sessions in total). The static passive resistive torque (PRT) of 45 degrees at the ankle joint was used as a measure of the joint stiffness, and was determined before and after the experimental period. After 10 sessions of eccentric exercise, the wet weight of medial gastrocnemius muscle significantly increased (P < 0.05), whereas the static PRT significantly decreased (P < 0.05) in the eccentric-exercise group, when compared to the sham-operated group. Myosin-ATPase staining showed a decrease in the number of type IIb/IId fibers (P < 0.001) and an increase in the number of type IIa fibers (P < 0.05). However, no significant difference was seen in the connectin (titin) isoform composition between the eccentric-exercise group and the sham-operated group, suggesting that the reduction in PRT was not due to change in resting mechanical properties of muscle fibers.
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PMID:Effects of eccentric exercise on joint stiffness and muscle connectin (titin) isoform in the rat hindlimb. 1708 53


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