Abstract. Titin (also known as connectin) is a giant protein that spans half of the striated muscle sarcomere. In the I-band titin extends as the sarcomere is stretched, developing what is known as passive force. The I-band region of titin contains tandem Ig segments (consisting of serially linked immunoglobulin-like domains) with the unique PEVK segment in between (Labeit, S., and B. Kolmerer. 1995. Science . 270:293-296). Although the tandem Ig and PEVK segments have been proposed to behave as stiff and compliant springs, respectively, precise experimental testing of the hypothesis is still needed. Here, sequence-specific antibodies were used to mark the ends of the tandem Ig and PEVK segments. By following the extension of the segments as a function of sarcomere length (SL), their respective contributions to titin's elastic behavior were established. In slack sarcomeres ( ف 2.0 m) the tandem Ig and PEVK segments were contracted. Upon stretching sarcomeres from ف 2.0 to 2.7 m, the "contracted" tandem Ig segments straightened while their individual Ig domains remained folded. When sarcomeres were stretched beyond ف 2.7 m, the tandem Ig segments did not further extend, instead PEVK extension was now dominant. Modeling tandem Ig and PEVK segments as entropic springs with different bending rigidities (Kellermayer, M., S. Smith, H. Granzier, and C. Bustamante. 1997. Science. 276:1112-1116 indicated that in the physiological SL range ( a ) the Ig-like domains of the tandem Ig segments remain folded and ( b ) the PEVK segment behaves as a permanently unfolded polypeptide. Our model provides a molecular basis for the sequential extension of titin's different segments. Initially, the tandem Ig segments extend at low forces due to their high bending rigidity. Subsequently, extension of the PEVK segment occurs only upon reaching sufficiently high external forces due to its low bending rigidity. The serial linking of tandem Ig and PEVK segments with different bending rigidities provides a unique passive force-SL relation that is not achievable with a single elastic segment.T itin is a giant filamentous protein that, in addition to the thin and thick filaments, constitutes the third myofilament system of striated muscle. In the sarcomere, titin molecules span the entire 1-2-m distance from the Z-line to the M-line. Previous studies have revealed that the A-band region of the molecule is rendered inextensible due to its tight association with the thick filament, whereas the I-band region behaves elastically as the sarcomere undergoes changes in length. The elastic properties of the I-band region of titin are primarily responsible for the passive force that is generated when unactivated (i.e., passive) muscle is stretched. Passive force is present in actively contracting muscle as well, where it helps maintain the structural integrity of the sarcomere and thereby ensures efficient muscle contraction. (For recent reviews and original citations see Fürst and Gautel, 1995;Trinick, 1996;Wang, 1996;Labeit et al., 1997;Maruy...
Actin-activated myosin II motor function powers muscle contraction and nonmuscle cell motility. The actin-myosin-derived contractility has evolved with a great diversity in different muscle and cell types. Actin filament-based regulation controls striated muscle contraction and plays a role in modulating smooth muscle contractility and nonmuscle cell motility. This review focuses on the isoform diversity and functional adaptations of troponin in striated muscle and calponin in smooth muscle and nonmuscle cells. The gene regulation, alternative RNA splicing, and posttranslational modifications of troponin I and troponin T are summarized, together with recent progress in calponin studies. The biologic significance of the structural and functional diversity and regulation of troponin and calponin is discussed for roles in normal contractility and diseases.
Troponin-mediated Ca 2+ -regulation governs the actin-activated myosin motor function which powers striated (skeletal and cardiac) muscle contraction. This review focuses on the structurefunction relationship of troponin T, one of the three protein subunits of the troponin complex. Molecular evolution, gene regulation, alternative RNA splicing, and posttranslational modifications of troponin T isoforms in skeletal and cardiac muscles are summarized with emphases on recent research progresses. The physiological and pathophysiological significances of the structural diversity and regulation of troponin T are discussed for impacts on striated muscle function and adaptation in health and diseases. Keywords troponin T isoform genes; molecular evolution; posttranscriptional modification; striated muscle thin filament; calcium regulation of contraction The contraction of striated muscle (represented by vertebrate skeletal and cardiac muscles) is powered by actin-activated myosin II ATPase. The contractile machinery in striated muscles is the numerous myofibrils that consist of serially connected contractile units called sarcomeres. A sarcomere is composed of overlapping myosin thick filaments and actin thin filaments. In vertebrate striated muscles, contraction is generated from ATP hydrolysis during actomyosin cross-bridge cycling that is regulated by intracellular Ca 2+ transient via the thin filament-associated proteins troponin and tropomyosin (1).Residing at ~37 nm intervals along the thin filament of F-actin-tropomyosin double helices (2,3,4), the troponin complex consists of three protein subunits: The Ca 2+ -binding subunit troponin C (TnC1), the actomyosin ATPase inhibiting subunit troponin I (TnI), and the tropomyosin-binding subunit troponin T (TnT) (5). The name of TnT was based on the original ultracentrifugation and co-crystallization studies that verified TnT interaction with tropomyosin as the key subunit holding the troponin complex on the thin filament (6).
Calponin is an extensively studied actin-binding protein, but its function is not well understood. Among three isoforms of calponin, h2-calponin is found in both smooth muscle and non-muscle cells. The present study demonstrates that epidermal keratinocytes and fibroblast cells express significant amounts of h2-calponin. The expression of h2-calponin is cell anchorage-dependent. The levels of h2-calponin decrease when cells are rounded up and remain low when cells are prevented from adherence to a culture dish. h2-calponin expression resumes after the floating cells are allowed to form a monolayer in plastic dish. Cell cultures on polyacrylamide gels of different stiffness demonstrated that h2-calponin expression is affected by the mechanical properties of the culture matrix. When cells are cultured on soft gel that applies less traction force to the cell and, therefore, lower mechanical tension in the cytoskeleton, the level of h2-calponin is significantly lower than that in cells cultured on hard gel or rigid plastic dish. Force-expression of h2-calponin enhanced the resistance of the actin filaments to cytochalasin B treatment. Keratinocyte differentiation is accompanied by a mechanical tension-related up-regulation of h2-calponin. Lowering the tension of actin cytoskeleton by inhibiting non-muscle myosin II ATPase decreased h2-calponin expression. In contrast to the mechanical tension regulation of endogenous h2-calponin, the expression of h2-calponin using a cytomegalovirus promotor was independent of the stiffness of culture matrix. The results suggest that h2-calponin represents a novel manifestation of mechanical tension responsive gene regulation that may modify cytoskeleton function.Calponin is a family of actin-associated proteins first found in smooth muscle cells (1). Three calponin isoforms (h1-, h2-, and acidic calponins) are encoded by three homologous genes. h1-calponin (2, 3) is specifically expressed in differentiated smooth muscle cells and has been extensively studied for its role in the regulation of smooth muscle contractility (for review, see Refs. 4 -6). The acidic calponin is found in nervous tissues and implicates in neuronal regeneration and growth (7-8).h2-calponin (3) is found in both smooth muscle and non-muscle cells such as human epidermal keratinocytes (9). h2-calponin mRNA has been also detected in endothelial cells (10) and fibroblasts (11). The gene regulation and function of h2-calponin are largely unknown. Previous studies suggested that h2-calponin may play a role in the organization of actin cytoskeleton (12) and in cytokinesis (13). This hypothesis is supported by the observation that h2-calponin is expressed at significant levels in growing and remodeling tissues (13). Forced expression of h2-calponin in cells lacking endogenous calponin results in an association with the actin stress fibers and a decrease in the rate of cell proliferation (13). These results suggest a microfilament-associated activity of h2-calponin, which may regulate the function of actin cytoskeleto...
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