Tissue-specific expression and α-actinin binding properties of the Z-disc titin: implications for the nature of vertebrate Z-discs

Sorimachi, Hiroyuki; Freiburg, Alexandra; Kolmerer, Bernhard; Ishiura, Shoichi; Stier, Günter; Gregorio, Carol C.; Labeit, D.; Linke, Wolfgang A.; Suzuki, Koichi; Labeit, Siegfried

doi:10.1006/jmbi.1997.1145

Cited by 190 publications

(225 citation statements)

References 40 publications

(38 reference statements)

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“…S1) (18, 19). Upon activation of α-actinin in the Z-disk by phosphatidylinositol 4,5-biphosphate (PIP 2 ), EF3-4 is released from the neck and binding of titin can be achieved in this open conformation of α-actinin.In humans, the isoforms of titin exhibit four to seven Z-repeats (15,16,20). The structure of the EF3-4 hands complex with titin Z-repeat 7 shows the bound Z-repeat in an α-helical conformation (21).…”

mentioning

confidence: 99%

α-Actinin/titin interaction: A dynamic and mechanically stable cluster of bonds in the muscle Z-disk

Grison

Merkel

Košťan

et al. 2017

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

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Stable anchoring of titin within the muscle Z-disk is essential for preserving muscle integrity during passive stretching. One of the main candidates for anchoring titin in the Z-disk is the actin crosslinker α-actinin. The calmodulin-like domain of α-actinin binds to the Z-repeats of titin. However, the mechanical and kinetic properties of this important interaction are still unknown. Here, we use a dual-beam optical tweezers assay to study the mechanics of this interaction at the single-molecule level. A single interaction of α-actinin and titin turns out to be surprisingly weak if force is applied. Depending on the direction of force application, the unbinding forces can more than triple. Our results suggest a model where multiple α-actinin/Z-repeat interactions cooperate to ensure long-term stable titin anchoring while allowing the individual components to exchange dynamically.M uscle is the tissue that is constantly subjected to high mechanical loads. Whereas thick and thin filaments are responsible for active force production, the passive elasticity of muscle is dominated by titin/connectin filaments (1). Hence, under passive stretching conditions the integrity of muscle relies on titin's being firmly anchored within the sarcomere, preventing the interdigitated muscle filaments from falling apart (Fig. 1A). Whereas titin is firmly attached to thick filaments in the A-band and the M-line (2-6), it is much less clear how stable anchoring is achieved in the Z-disk, where adjacent sarcomeres overlap. The superstable titin/telethonin interaction within the Z-disk was considered important for titin anchoring (7-9), but knockout mutants later showed that it is not essential for muscle integrity (10-12). Apart from a direct interaction between actin filaments and titin at the Z-disk edge (13), the most prominent candidate for the anchoring of titin within the Z-disk is its interaction with α-actinin (Fig. 1B) (6,12,14).Four isoforms of human α-actinin have been identified: the calcium-insensitive muscle isoforms 2 and 3, which cross-link actin filaments in sarcomere-delimiting Z-disk complexes, and calcium-sensitive nonmuscle isoforms 1 and 4. α-Actinin is an antiparallel homodimer whose most prominent task is crosslinking actin filaments of neighboring sarcomeres in the Z-disk ( Fig. 1B; reviewed in ref. 14). In each subunit, a flexible region called the neck separates the actin binding domain (ABD) from four spectrin-like repeats (SR) forming the rod region (Fig. 1B and Fig. S1). The rod regions of the two subunits interact and provide a rigid spacer between the actin filaments. At the other end of each subunit a calmodulin-like domain (CaMD) formed by two pairs of EF-hands (EF1-2 and EF3-4) is able to bind a Z-disk region of titin formed by the so-called Z-repeats (15-17). The current model for α-actinin 2 dynamic regulation suggests that EF3-4 hands of one subunit bind to the neck region of the juxtaposed subunit, thus not being available for the interaction with titin Z-repeats (Fig. S1) (18, 19). Upon activ...

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mentioning

confidence: 99%

α-Actinin/titin interaction: A dynamic and mechanically stable cluster of bonds in the muscle Z-disk

Grison

Merkel

Košťan

et al. 2017

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

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“…However, the CaM domain in muscle is not able to bind calcium. As is described later, several Z-disc proteins have been reported to bind ®-actinin 2, including nebulin (14 ), ALP (15 ), FATZ (16 ), myotilin (17 ), titin (18)(19)(20), and ZASP (21).…”

Section: Z-disc Proteinsmentioning

confidence: 90%

“…The difference in number of alternatively spliced repeats in titin isoforms has been suggested to affect the number of cross-links between ®-actinin 2 and F-actin laments (22) and hence to cause variation in Z-disc thickness (23). There appear to be two types of binding sites for titin in ®-actinin 2: 1) the C-terminal CaM domain that interacts with several z-repeats of titin (4,19,20); 2) the zq-Z4 region that binds to two spectrin-like repeats (R2 and R3).…”

Section: Z-disc Proteinsmentioning

confidence: 99%

“…These Ig-like titin domains and the C-terminal of myotilin are located at the periphery of the Z-disc; therefore, they could share motifs for Z-disc localization (20). Myotilin binds via its N-terminal region (79-150 amino acid residues) to the C-terminal spectrin-like repeats 3 and 4 of ®-actinin 2 (17 ), whereas it binds via its C-terminal two Ig-like domains to the N-terminal domain of°-lamin (39).…”

Section: Z-disc Proteinsmentioning

confidence: 99%

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Telethonin and Other New Proteins of the Z‐Disc of Skeletal Muscle

Faulkner

Lanfranchi²,

Valle³

2001

IUBMB Life

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“…An attractive model suggests that their binding to ␣-actinin may fine tune the actin cross-linking property of ␣-actinin and this hypothesis is supported by research demonstrating that addition of ALP to an ␣-actininactin mixture significantly enhances their co-sedimentation in vitro (Pashmforoush et al, 2001). Titin, whose amino terminus spans the Z-disk, also binds ␣-actinin (Sorimachi et al, 1997;Gregorio et al, 1998). This interaction may account for the varying width of Z-disks by regulating the number of cross-links mediated by ␣-actinin (Young et al, 1998).…”

Section: The Z-disk As a Focal Point For Force Propagationmentioning

confidence: 98%

Molecular mechanisms of mechanosensing in muscle development

Jani

Schöck

2009

Developmental Dynamics

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Mechanical forces are crucial to muscle development and function, but the mechanisms by which forces are sensed and transduced remain elusive. Evidence implicates the sarcolemmal lattice of integrin adhesion and the Z-disk components of the contractile machinery in such processes. These mechanosensory devices report changes in force to other cellular compartments by self-remodeling. Here we explore how their structural and functional properties integrate to regulate muscle development and maintenance.

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Tissue-specific expression and α-actinin binding properties of the Z-disc titin: implications for the nature of vertebrate Z-discs

Cited by 190 publications

References 40 publications

α-Actinin/titin interaction: A dynamic and mechanically stable cluster of bonds in the muscle Z-disk

α-Actinin/titin interaction: A dynamic and mechanically stable cluster of bonds in the muscle Z-disk

Telethonin and Other New Proteins of the Z‐Disc of Skeletal Muscle

Molecular mechanisms of mechanosensing in muscle development

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