Interaction of Dystrophin with Cytoskeletal Proteins: Binding to Talin and Actin

Senter, L.; Luise, Monica De; Presotto, Cristina; Betto, Romeo; Teresi, A.; Ceoldo, Stefania; Salviati, G.

doi:10.1006/bbrc.1993.1500

Cited by 52 publications

(30 citation statements)

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“…This facilitated the discovery of how efficiently the Dys-ABD colocalized with filaments formed by the overexpression of K8 and K19. The association of the Dys-ABD with actin in endogenous stress fibers and at the plasma membrane of most COS-7 cells is consistent with in vitro studies of its ability to bind to actin and to cross-link microfilaments (Senter et al, 1993;Renley et al, 1998;Sutherland-Smith et al, 2003). Despite its cross-linking activity, linked to its ability to dimerize (Sutherland-Smith et al, 2003), the Dys-ABD does not significantly alter the organization of K8/K19 filaments, suggesting that the Dys-ABD does not cross-link these filaments to each other.…”

Section: Discussionsupporting

confidence: 80%

“…Although DS-Red accumulated in the nucleus ( Figure 1J), it reached significant levels in the cytoplasm and so could be detected if it were concentrated at actin-rich structures. Thus, under otherwise normal conditions, the DS-Red fusion protein of the Dys-ABD preferentially associated with actin-rich structures in the cytoplasm of COS-7 cells, consistent with the ability of the Dys-ABD to associate with actin filaments in vitro (Senter et al, 1993;Renley et al, 1998;Orlova et al, 2001). …”

Section: Dys-abd Associates Specifically With Filaments Containing K8supporting

confidence: 66%

“…We repeated these experiments eight times, The fact that the His-Dys-ABD binds to purified K19 on the surface of the chip as well as to hK19 in soluble extracts of COS-7 cells, suggests that the Dys-ABD interacts directly with this cytokeratin subunit. The rapid time course of binding and dissociation of the his-Dys-ABD to the surface of the biosensor chip charged with K19, as well as the high concentrations of the fusion protein required to observe binding, are consistent with affinities in the micromolar range or higher, the same range documented for the binding of the Dys-ABD to actin (Senter et al, 1993;Winder et al, 1995;Renley et al, 1998;Sutherland-Smith et al, 2003). …”

supporting

confidence: 57%

“…Values in the low micromolar range are consistent with the rapid on-and off-rates for binding observed in surface plasmon resonance experiments at the micromolar concentrations of reagents we used (Figure 6) as well as with the results of our dot blots. This range is comparable to the affinity of the Dys-ABD for actin filaments of ϳ10 -50 M (Senter et al, 1993;Winder et al, 1995;Renley et al, 1998;Sutherland-Smith et al, 2003). The affinity of intact, fulllength dystrophin for actin is considerably higher, due to the presence of clusters of basic residues in its spectrin repeat region that greatly enhance actin binding Warner et al, 2002).…”

Section: Discussionmentioning

confidence: 60%

“…Dystrophin binds actin (Senter et al, 1993;Renley et al, 1998;Sutherland-Smith et al, 2003), and this activity is thought to be physiologically important for the health of the muscle fiber (Corrado et al, 1996;Eraslan et al, 1999;Warner et al, 2002). In healthy muscle, fragments of sarcolemma can be isolated that are linked to filamentous actin at costameres, but this actin is lost from sarcolemmal fragments isolated from muscle lacking dystrophin (Rybakova et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

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Specific Interaction of the Actin-binding Domain of Dystrophin with Intermediate Filaments Containing Keratin 19

Stone

O’Neill

Catino

et al. 2005

MBoC

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Cytokeratins 8 and 19 concentrate at costameres of striated muscle and copurify with the dystrophin-glycoprotein complex, perhaps through the interaction of the cytokeratins with the actin-binding domain of dystrophin. We overexpressed dystrophin's actin-binding domain (Dys-ABD), K8 and K19, as well as closely related proteins, in COS-7 cells to assess the basis and specificity of their interaction. Dys-ABD alone associated with actin microfilaments. Expressed with K8 and K19, which form filaments, Dys-ABD associated preferentially with the cytokeratins. This interaction was specific, as the homologous ABD of ␤I-spectrin failed to interact with K8/K19 filaments, and Dys-ABD did not associate with desmin or K8/K18 filaments. Studies in COS-7 cells and in vitro showed that Dys-ABD binds directly and specifically to K19. Expressed in muscle fibers in vivo, K19 accumulated in the myoplasm in structures that contained dystrophin and spectrin and disrupted the organization of the sarcolemma. K8 incorporated into sarcomeres, with no effect on the sarcolemma. Our results show that dystrophin interacts through its ABD with K19 specifically and are consistent with the idea that cytokeratins associate with dystrophin at the sarcolemma of striated muscle. INTRODUCTIONMutations in the gene for dystrophin cause Duchenne or Becker Muscular Dystrophy, but we still know little about dystrophin's functions in normal muscle or how its absence leads to the loss of myofibers. Dystrophin is the major cytoskeletal component of a large, transmembrane complex (Ahn and Kunkel, 1993;Matsumura and Campbell, 1994;Ozawa et al., 1998) that plays a role in signaling from the plasma membrane of skeletal myofibers (sarcolemma) to the cytoplasm (Rando, 2001;Lapidos et al., 2004) and in transmitting the force of contraction across the sarcolemma to extracellular structures (Campbell, 1995;Bloch and Gonzalez-Serratos, 2003). Here, we focus on the latter role, and particularly, on the nature of the connections made between the contractile apparatus and the sarcolemma, at sites termed "costameres" (Bloch and Gonzalez-Serratos, 2003;Ervasti, 2003).Costameres are riblike structures that surround each myofiber at the sarcolemma and that are enriched in a number of integral and peripheral membrane proteins (Bloch and Gonzalez-Serratos, 2003;Ervasti, 2003), including dystrophin (Masuda et al., 1992;Minetti et al., 1992;Porter et al., 1992;Straub et al., 1992;Williams and Bloch, 1999a;Rybakova et al., 2000). Costameres and the connections between the contractile apparatus and the sarcolemma that they anchor are present at the plasma membrane overlying both the Z and M lines of superficial myofibrils of fast-twitch muscles (Porter et al., 1992;Williams et al., 2000). They also can be oriented at the plasma membrane parallel to the longitudinal axis of the myofibers, creating a rectilinear, structural lattice at the sarcolemma. Dystrophin and its associated proteins are enriched at all these sites (Porter et al., 1992;Williams and Bloch, 1999a;Williams et al...

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Section: Discussionsupporting

confidence: 80%

Section: Dys-abd Associates Specifically With Filaments Containing K8supporting

confidence: 66%

supporting

confidence: 57%

Section: Discussionmentioning

confidence: 60%

Section: Introductionmentioning

confidence: 99%

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Specific Interaction of the Actin-binding Domain of Dystrophin with Intermediate Filaments Containing Keratin 19

Stone

O’Neill

Catino

et al. 2005

MBoC

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Talin2 is induced during striated muscle differentiation and is targeted to stable adhesion complexes in mature muscle

Senetar

Moncman

McCann

2006

Cell Motil. Cytoskeleton

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The cytoskeletal protein talin serves as an essential link between integrins and the actin cytoskeleton in several similar, but functionally distinct, adhesion complexes, including focal adhesions, costameres, and intercalated disks. Vertebrates contain two talin genes, TLN1 and TLN2, but the different roles of Talin1 and Talin2 in cell adhesion are unclear. In this report we have analyzed Talin1 and Talin2 in striated muscle. Using isoform-specific antibodies, we found that Talin2 is highly expressed in mature striated muscle. Using mouse C2C12 cells and primary human skeletal muscle myoblasts as models of muscle differentiation, we show that Talin1 is expressed in undifferentiated myoblasts and that Talin2 expression is upregulated during muscle differentiation at both the mRNA and protein levels. We have also identified regulatory sequences that may be responsible for the differential expression of Talin1 and Talin2. Using GFP-tagged Talin1 and Talin2 constructs, we found that GFP-Talin1 targets to focal adhesions while GFP-Talin2 targets to abnormally large adhesions in myoblasts. We also found that ectopic expression of Talin2 in myoblasts, which do not contain appreciable levels of Talin2, dysregulates the actin cytoskeleton. Finally we demonstrate that Talin2, but not Talin1, localizes to costameres and intercalated disks, which are stable adhesions required for the assembly of mature striated muscle. Our results suggest that Talin1 is the primary link between integrins and actin in dynamic focal adhesions in undifferentiated, motile cells, but that Talin2 may serve as the link between integrins and the sarcomeric cytoskeletonin stable adhesion complexes in mature striated muscle.

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Evolving paradigms in clinical pharmacology and therapeutics for the treatment of Duchenne muscular dystrophy

Huard

Lü

2016

Clin Pharma and Therapeutics

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Progressive muscle weakness and degeneration due to the lack of dystrophin eventually leads to the loss of independent ambulation by the middle of the patient's second decade, and a fatal outcome due to cardiac or respiratory failure by the third decade. More specifically, loss of sarcolemmal dystrophin and the dystrophin-associated glycoprotein (DAG) complex promotes muscle fiber damage during muscle contraction. This process results in an efflux of creatine kinase (CK), an influx of calcium ions, and the recruitment of T cells, macrophages, and mast cells to the damaged muscle, causing progressive myofiber necrosis. For the last 20 years, the major goal in the development of therapeutic approaches to alleviate muscle weakness in DMD has been centered on the restoration of dystrophin or proteins that are analogous to dystrophin, such as utrophin, through a variety of modalities including cell therapy, gene therapy, gene correction, and the highly promising techniques utilizing CRISPR/Cas9 technology. Despite the development of new therapeutic options, there still exist numerous challenges that we must face with regard to these new strategies and, consequently, we still do not have any feasible options available to ultimately slow the progression of this devastating disease. The purpose of this article is to highlight the current knowledge and advancements in the evolving paradigms in clinical pharmacology and therapeutics for this devastating musculoskeletal disease.

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Interaction of Dystrophin with Cytoskeletal Proteins: Binding to Talin and Actin

Cited by 52 publications

References 0 publications

Specific Interaction of the Actin-binding Domain of Dystrophin with Intermediate Filaments Containing Keratin 19

Specific Interaction of the Actin-binding Domain of Dystrophin with Intermediate Filaments Containing Keratin 19

Talin2 is induced during striated muscle differentiation and is targeted to stable adhesion complexes in mature muscle

Evolving paradigms in clinical pharmacology and therapeutics for the treatment of Duchenne muscular dystrophy

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