The structure of the N-terminal actin-binding domain of human dystrophin and how mutations in this domain may cause Duchenne or Becker muscular dystrophy

Norwood, Fiona; Sutherland-Smith, Andrew J.; Keep, Nicholas H.; Kendrick‐Jones, John

doi:10.1016/s0969-2126(00)00132-5

Cited by 153 publications

(178 citation statements)

References 58 publications

Supporting

Mentioning

169

Contrasting

Order By: Relevance

“…The I/LE(G)L motif of the Dys-ABD, contained in its third or C-helix, has not been implicated in actin binding (Norwood et al, 2000;Gimona et al, 2002), nor is it present in human actins. It contains two residues, Q45 and D52, that distinguish it from the homologous region in the ABD of ␤I-spectrin and that may account in part for its preference for the cytokeratins.…”

Section: Discussionmentioning

confidence: 98%

“…Structural studies show that the sequences containing the I/LE(G)L motifs of the Dys-ABD, K8, and K19 are all helical, although the flanking N-and C-terminal residues in the Dys-ABD are in nonhelical linkers (Norwood et al, 2000). The I/LE(G)L motif of the Dys-ABD, contained in its third or C-helix, has not been implicated in actin binding (Norwood et al, 2000;Gimona et al, 2002), nor is it present in human actins.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

Stone

O’Neill

Catino

et al. 2005

MBoC

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

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

Stone

O’Neill

Catino

et al. 2005

MBoC

View full text Add to dashboard Cite

show abstract

“…All substitutions (except L172F) lie on one face of the domain (Fig. 4), and those within helix A map to a region previously implicated in actin binding 22 . Similarly distributed mutations in the dystrophin CHD2 are associated with residual function (Becker phenotype), and those in α-actinin-4 were proposed to enhance actin binding 21 .…”

mentioning

confidence: 86%

“…3). We modeled the tertiary structure of the CHD2 domain of filamin A based on sequence homology to the previously obtained structures of the CHD2 in dystrophin 22 and β-spectrin 23 . Most notably, the recurrent OPD2 mutation E254K is predicted to disrupt a highly conserved salt bridge with residue Lys169 (Figs.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans

et al. 2003

Self Cite

View full text Add to dashboard Cite

Remodeling of the cytoskeleton is central to the modulation of cell shape and migration. Filamin A, encoded by the gene FLNA, is a widely expressed protein that regulates re-organization of the actin cytoskeleton by interacting with integrins, transmembrane receptor complexes and second messengers 1,2 . We identified localized mutations in FLNA that conserve the reading frame and lead to a broad range of congenital malformations, affecting craniofacial structures, skeleton, brain, viscera and urogenital tract, in four X-linked human disorders: otopalatodigital syndrome types 1 (OPD1; OMIM 311300) and 2 (OPD2; OMIM 304120), frontometaphyseal dysplasia (FMD; OMIM 305620) and Melnick-Needles syndrome (MNS; OMIM 309350). Several mutations are recurrent, and all are clustered into four regions of the gene: the actin-binding domain and rod domain repeats 3, 10 and 14/15. Our findings contrast with previous observations that loss of function of FLNA is embryonic lethal in males but manifests in females as a localized neuronal migration disorder, called periventricular nodular heterotopia (PVNH; refs. 3-6). The patterns of mutation, X-chromosome inactivation and phenotypic manifestations in the newly described mutations indicate that they have gain-of-function effects, implicating filamin A in signaling pathways that mediate organogenesis in multiple systems during embryonic development.

show abstract

Pleckstrin Homology ( PH ) Domains

Márquez

Saraste

2002

Wiley Encyclopedia of Molecular Medicine

View full text Add to dashboard Cite

The structure of the N-terminal actin-binding domain of human dystrophin and how mutations in this domain may cause Duchenne or Becker muscular dystrophy

Cited by 153 publications

References 58 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

Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans

Pleckstrin Homology ( PH ) Domains

Contact Info

Product

Resources

About