Titin: properties and family relationships

Tskhovrebova, Larissa; Trinick, John

doi:10.1038/nrm1198

Cited by 321 publications

(291 citation statements)

References 124 publications

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“…In the vertebrate muscle sarcomere, titin serves as a molecular ruler for sarcomere assembly and is responsible for resting elasticity of muscle (1,2) (Fig. 1A).…”

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confidence: 99%

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Mechanoenzymatics of titin kinase

Puchner

Alexandrovich

Kho

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

313

332

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Biological responses to mechanical stress require strain-sensing molecules, whose mechanically induced conformational changes are relayed to signaling cascades mediating changes in cell and tissue properties. In vertebrate muscle, the giant elastic protein titin is involved in strain sensing via its C-terminal kinase domain (TK) at the sarcomeric M-band and contributes to the adaptation of muscle in response to changes in mechanical strain. TK is regulated in a unique dual autoinhibition mechanism by a C-terminal regulatory tail, blocking the ATP binding site, and tyrosine autoinhibition of the catalytic base. For access to the ATP binding site and phosphorylation of the autoinhibitory tyrosine, the C-terminal autoinhibitory tail needs to be removed. Here, we use AFM-based single-molecule force spectroscopy, molecular dynamics simulations, and enzymatics to study the conformational changes during strain-induced activation of human TK. We show that mechanical strain activates ATP binding before unfolding of the structural titin domains, and that TK can thus act as a biological force sensor. Furthermore, we identify the steps in which the autoinhibition of TK is mechanically relieved at low forces, leading to binding of the cosubstrate ATP and priming the enzyme for subsequent autophosphorylation and substrate turnover.

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“…In the vertebrate muscle sarcomere, titin serves as a molecular ruler for sarcomere assembly and is responsible for resting elasticity of muscle (1,2) (Fig. 1A).…”

mentioning

confidence: 99%

“…Because titin is firmly embedded in the contractile machinery ( Fig. 1 A), its conformation and function can readily be affected by mechanical forces (1,6). The M-band, being much more compliant than the Z-disk (7,8), is ideally placed as a strain sensor (9,10).…”

mentioning

confidence: 99%

Mechanoenzymatics of titin kinase

Puchner

Alexandrovich

Kho

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

313

332

View full text Add to dashboard Cite

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“…A significant progress in this field resulted from the studies of the third filament system of sarcomeres formed by titin and its associated proteins that extend from the Z-discs to M-lines of myofibrils (Tskhovrebova and Trinick 2003;Granzier and Labeit 2005). It was demonstrated that two giant muscle proteins, titin and nebulin/nebulette, are involved in patterning and defining the spatial dimensions of sarcomere compartments, ensuring the elasticity of myofibrils.…”

Section: Introductionmentioning

confidence: 99%

Early incorporation of obscurin into nascent sarcomeres: implication for myofibril assembly during cardiac myogenesis

Borisov

Martynova

Russell

2008

Histochem Cell Biol

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Obscurin is a recently identified giant multidomain muscle protein whose functions remain poorly understood. The goal of this study was to investigate the process of assembly of obscurin into nascent sarcomeres during the transition from non-striated myofibril precursors to striated structure of differentiating myofibrils in cell cultures of neonatal rat cardiac myocytes. Double immunofluorescent labeling and high resolution confocal microscopy demonstrated intense incorporation of obscurin in the areas of transition from non-striated to striated regions on the tips of developing myofibrils and at the sites of lateral fusion of nascent sarcomere bundles. We found that obscurin rapidly and precisely accumulated in the middle of the A-band regions of the terminal newly assembled half-sarcomeres in the zones of transition from the continuous, non-striated pattern of sarcomeric α-actinin distribution to cross-striated structure of laterally expanding nascent Z-discs. The striated pattern of obscurin typically ended at these points. This occurred before the assembly of morphologically differentiated terminal Z-discs of the assembling sarcomeres on the tips of growing myofibrils. The presence of obscurin in the areas of the terminal Z-discs of each new sarcomere was detected at the same time or shortly after complete assembly of sarcomeric structure. Many non-striated fibers with very low concentration of obscurin were already immunopositive for sarcomeric actin and myosin. This suggests that obscurin may serve for organization and alignment of myofilaments into the striated pattern. The comparison of obscurin and titin localization in these areas showed that obscurin assembly into the A-bands occurred soon after or concomitantly with incorporation of titin. Electron microscopy of growing myofibrils demonstrated intense formation and integration of myosin filaments into the "open" half-assembled sarcomeres in the areas of the terminal Z-I structures and at the lateral surfaces of newly formed, terminally located nascent sarcomeres. This process progressed before the assembly of the second-formed, terminal Z-discs of new sarcomeres and before the development of ultrastructurally detectable mature M-lines that define the completion of myofibril assembly, which supports the data of immunocytochemical study. Abundant non-aligned sarcomeres in immature myofibrils located on the growing tips were spatially separated and underwent the transition to the registered, aligned pattern. The sarcoplasmic reticulum, © Springer-Verlag 2008 aborisov@umich.edu. This paper is dedicated to the memory of Professor Pavel P. Rumyantsev (1927Rumyantsev ( -1988, a pioneer in studies of cardiac muscle differentiation, who is a lasting inspiration to all who worked with him. the organelle known to interact with obscurin, assembled around each new sarcomere. These results suggest that obscurin is directly involved in the proper positioning and alignment of myofilaments within nascent sarcomeres and in the establishment of the registered ...

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“…Long equilibrium simulations for G5 2 and E-G5 2 were carried out using a coarse-grained native-centric model, which allowed us to follow a number of unfolding and folding reactions. In all of these simulations, the first step in the folding of both G5 2 and E-G5 2 is formation of the C-terminal β-sheet/loop motif of G5 2 (Fig. 3).…”

Section: Kinetic Experiments Reveal That Sasg Domains Fold and Unfoldmentioning

confidence: 99%

“…Some proteins function as a consequence of disorder: for example, disordered PEVK regions of titin act as an entropic spring (2), whereas in the nuclear pore complex, disordered nucleoporins provide a thick selective barrier controlling nuclear import (3). Disorder can also play other roles: it facilitates posttranslational modification and may promote allostery (4,5).…”

mentioning

confidence: 99%

Disorder drives cooperative folding in a multidomain protein

Gruszka

Mendonca

Paci

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Many human proteins contain intrinsically disordered regions, and disorder in these proteins can be fundamental to their function-for example, facilitating transient but specific binding, promoting allostery, or allowing efficient posttranslational modification. SasG, a multidomain protein implicated in host colonization and biofilm formation in Staphylococcus aureus, provides another example of how disorder can play an important role. Approximately one-half of the domains in the extracellular repetitive region of SasG are intrinsically unfolded in isolation, but these E domains fold in the context of their neighboring folded G5 domains. We have previously shown that the intrinsic disorder of the E domains mediates long-range cooperativity between nonneighboring G5 domains, allowing SasG to form a long, rod-like, mechanically strong structure. Here, we show that the disorder of the E domains coupled with the remarkable stability of the interdomain interface result in cooperative folding kinetics across long distances. Formation of a small structural nucleus at one end of the molecule results in rapid structure formation over a distance of 10 nm, which is likely to be important for the maintenance of the structural integrity of SasG. Moreover, if this normal folding nucleus is disrupted by mutation, the interdomain interface is sufficiently stable to drive the folding of adjacent E and G5 domains along a parallel folding pathway, thus maintaining cooperative folding.IDP | protein folding | parallel pathways | protein engineering | cooperativity I t has been suggested that as much as 20% of the proteome may be intrinsically disordered (1), mainly manifested as intrinsically disordered regions within multidomain proteins, although a few proteins are apparently entirely disordered. Some proteins function as a consequence of disorder: for example, disordered PEVK regions of titin act as an entropic spring (2), whereas in the nuclear pore complex, disordered nucleoporins provide a thick selective barrier controlling nuclear import (3). Disorder can also play other roles: it facilitates posttranslational modification and may promote allostery (4, 5). SasG (Staphylococcus aureus surface protein G) is a cell wall-attached protein from S. aureus that promotes intercellular adhesion during the accumulation phase of biofilm formation via its C-terminal repetitive region (6-8). We previously showed that this part of SasG contains alternating E and G5 domains (Fig. 1A) and that E folds when it is N-terminal of a G5 domain. The disorder of E domains in isolation is essential for formation of a long, stiff, mechanically strong, rod-like structure (9) capable of projecting the N-terminal A domain, which is involved in host colonization (6).Here, we combine biophysical measurements, protein engineering, and simulation to show that the disorder in the E domains of SasG also promotes cooperative folding and unfolding pathways. We find that SasG domains have a highly polarized transition-state (TS) structure, where formation of a sm...

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Titin: properties and family relationships

Cited by 321 publications

References 124 publications

Mechanoenzymatics of titin kinase

Mechanoenzymatics of titin kinase

Early incorporation of obscurin into nascent sarcomeres: implication for myofibril assembly during cardiac myogenesis

Disorder drives cooperative folding in a multidomain protein

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