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PDBsum entry 1dxx
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Structural protein PDB id
1dxx

 

 

 

 

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Contents
Protein chains
238 a.a. *
Waters ×74
* Residue conservation analysis
PDB id:
1dxx
Name: Structural protein
Title: N-terminal actin-binding domain of human dystrophin
Structure: Dystrophin. Chain: a, b, c, d. Fragment: actin-binding. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Tissue: muscle. Cellular_location: cell membrane. Gene: dmd. Expressed in: escherichia coli. Expression_system_taxid: 469008.
Biol. unit: Tetramer (from PQS)
Resolution:
2.60Å     R-factor:   0.232     R-free:   0.268
Authors: F.L.Norwood,A.J.Sutherland-Smith,N.H.Keep,J.Kendrick-Jones
Key ref:
F.L.Norwood et al. (2000). 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. Structure, 8, 481-491. PubMed id: 10801490 DOI: 10.1016/S0969-2126(00)00132-5
Date:
20-Jan-00     Release date:   16-May-00    
PROCHECK
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 Headers
 References

Protein chains
Pfam   ArchSchema ?
P11532  (DMD_HUMAN) -  Dystrophin from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		3685 a.a.
238 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 2 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.?
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

 

 
DOI no: 10.1016/S0969-2126(00)00132-5 Structure 8:481-491 (2000)
PubMed id: 10801490  
 
 
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.
F.L.Norwood, A.J.Sutherland-Smith, N.H.Keep, J.Kendrick-Jones.
 
  ABSTRACT  
 
BACKGROUND: Dystrophin is an essential component of skeletal muscle cells. Its N-terminal domain binds to F-actin and its C terminus binds to the dystrophin-associated glycoprotein (DAG) complex in the membrane. Dystrophin is therefore thought to serve as a link from the actin-based cytoskeleton of the muscle cell through the plasma membrane to the extracellular matrix. Pathogenic mutations in dystrophin result in Duchenne or Becker muscular dystrophy. RESULTS: The crystal structure of the dystrophin actin-binding domain (ABD) has been determined at 2.6 A resolution. The structure is an antiparallel dimer of two ABDs each comprising two calponin homology domains (CH1 and CH2) that are linked by a central alpha helix. The CH domains are both alpha-helical globular folds. Comparisons with the structures of utrophin and fimbrin ABDs reveal that the conformations of the individual CH domains are very similar to those of dystrophin but that the arrangement of the two CH domains within the ABD is altered. The dystrophin dimer reveals a change of 72 degrees in the orientation of one pair of CH1 and CH2 domains (from different monomers) relative to the other pair when compared with the utrophin dimer. The dystrophin monomer is more elongated than the fimbrin ABD. CONCLUSIONS: The dystrophin ABD structure reveals a previously uncharacterised arrangement of the CH domains within the ABD. This observation has implications for the mechanism of actin binding by dystrophin and related proteins. Examining the position of three pathogenic missense mutations within the structure suggests that they exert their effects through misfolding of the ABD, rather than through disruption of the binding to F-actin.
 
  Selected figure(s)  
 
Figure 5.
Figure 5. Pathogenic missense mutations in the dystrophin ABD. (a) Stereoview of the environment of Leu54. (b) Stereoview of the 2F[o]-F[c] electron-density map in the region of Leu54. The electron-density map is contoured at 1.0s. (c) Stereoview of the environment of Ala168, Ala171 and Tyr231. The mutated residues are coloured red, with neighbouring hydrophobic sidechains coloured green. (d) Schematic representation of the dystrophin ABD sequence. The upper representation shows the actin-binding and mutation sites and the lower shows the exon boundaries.
 
  The above figure is reprinted by permission from Cell Press: Structure (2000, 8, 481-491) copyright 2000.  
  Figure was selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20457930 D.M.Henderson, A.Lee, and J.M.Ervasti (2010).
Disease-causing missense mutations in actin binding domain 1 of dystrophin induce thermodynamic instability and protein aggregation.
  Proc Natl Acad Sci U S A, 107, 9632-9637.  
20446344 S.H.Lee, and R.Dominguez (2010).
Regulation of actin cytoskeleton dynamics in cells.
  Mol Cells, 29, 311-325.  
20696926 S.M.Singh, N.Kongari, J.Cabello-Villegas, and K.M.Mallela (2010).
Missense mutations in dystrophin that trigger muscular dystrophy decrease protein stability and lead to cross-beta aggregates.
  Proc Natl Acad Sci U S A, 107, 15069-15074.  
20383143 V.E.Galkin, A.Orlova, A.Salmazo, K.Djinovic-Carugo, and E.H.Egelman (2010).
Opening of tandem calponin homology domains regulates their affinity for F-actin.
  Nat Struct Mol Biol, 17, 614-616.
PDB code: 3lue
19206170 O.L.Gurvich, B.Maiti, R.B.Weiss, G.Aggarwal, M.T.Howard, and K.M.Flanigan (2009).
DMD exon 1 truncating point mutations: amelioration of phenotype by alternative translation initiation in exon 6.
  Hum Mutat, 30, 633-640.  
19158079 S.Legardinier, B.Legrand, C.Raguénès-Nicol, A.Bondon, S.Hardy, C.Tascon, E.Le Rumeur, and J.F.Hubert (2009).
A Two-amino Acid Mutation Encountered in Duchenne Muscular Dystrophy Decreases Stability of the Rod Domain 23 (R23) Spectrin-like Repeat of Dystrophin.
  J Biol Chem, 284, 8822-8832.  
19367636 S.Tuffery-Giraud, C.Béroud, F.Leturcq, R.B.Yaou, D.Hamroun, L.Michel-Calemard, M.P.Moizard, R.Bernard, M.Cossée, P.Boisseau, M.Blayau, I.Creveaux, A.Guiochon-Mantel, B.de Martinville, C.Philippe, N.Monnier, E.Bieth, P.K.Van Kien, F.O.Desmet, V.Humbertclaude, J.C.Kaplan, J.Chelly, and M.Claustres (2009).
Genotype-phenotype analysis in 2,405 patients with a dystrophinopathy using the UMD-DMD database: a model of nationwide knowledgebase.
  Hum Mutat, 30, 934-945.  
18952167 B.Sjöblom, J.Ylänne, and K.Djinović-Carugo (2008).
Novel structural insights into F-actin-binding and novel functions of calponin homology domains.
  Curr Opin Struct Biol, 18, 702-708.  
19169097 E.M.Strehle (2008).
Dysferlinopathy: from gene to protein.
  J Clin Neuromuscul Dis, 10, 83-84.  
18164029 S.H.Lee, A.Weins, D.B.Hayes, M.R.Pollak, and R.Dominguez (2008).
Crystal structure of the actin-binding domain of alpha-actinin-4 Lys255Glu mutant implicated in focal segmental glomerulosclerosis.
  J Mol Biol, 376, 317-324.
PDB code: 2r0o
17222516 C.Antolik, D.H.Catino, A.M.O'Neill, W.G.Resneck, J.A.Ursitti, and R.J.Bloch (2007).
The actin binding domain of ACF7 binds directly to the tetratricopeptide repeat domains of rapsyn.
  Neuroscience, 145, 56-65.  
16752402 C.Farrington-Rock, M.H.Firestein, L.S.Bicknell, A.Superti-Furga, C.A.Bacino, V.Cormier-Daire, M.Le Merrer, C.Baumann, J.Roume, P.Rump, J.B.Verheij, E.Sweeney, D.L.Rimoin, R.S.Lachman, S.P.Robertson, D.H.Cohn, and D.Krakow (2006).
Mutations in two regions of FLNB result in atelosteogenesis I and III.
  Hum Mutat, 27, 705-710.  
16496225 R.A.Draviam, B.Wang, J.Li, X.Xiao, and S.C.Watkins (2006).
Mini-dystrophin efficiently incorporates into the dystrophin protein complex in living cells.
  J Muscle Res Cell Motil, 27, 53-67.  
15826935 I.N.Rybakova, and J.M.Ervasti (2005).
Identification of spectrin-like repeats required for high affinity utrophin-actin interaction.
  J Biol Chem, 280, 23018-23023.  
16000376 M.R.Stone, A.O'Neill, D.Catino, and R.J.Bloch (2005).
Specific interaction of the actin-binding domain of dystrophin with intermediate filaments containing keratin 19.
  Mol Biol Cell, 16, 4280-4293.  
15917206 S.P.Robertson (2005).
Filamin A: phenotypic diversity.
  Curr Opin Genet Dev, 15, 301-307.  
15960882 V.Delanote, J.Vandekerckhove, and J.Gettemans (2005).
Plastins: versatile modulators of actin organization in (patho)physiological cellular processes.
  Acta Pharmacol Sin, 26, 769-779.  
15272162 C.H.Wang, M.K.Balasubramanian, and T.Dokland (2004).
Structure, crystal packing and molecular dynamics of the calponin-homology domain of Schizosaccharomyces pombe Rng2.
  Acta Crystallogr D Biol Crystallogr, 60, 1396-1403.
PDB codes: 1p2x 1p5s
15274909 E.H.Egelman (2004).
More insights into structural plasticity of actin binding proteins.
  Structure, 12, 909-910.  
15128297 J.Sevcík, L.Urbániková, J.Kost'an, L.Janda, and G.Wiche (2004).
Actin-binding domain of mouse plectin. Crystal structure and binding to vimentin.
  Eur J Biochem, 271, 1873-1884.
PDB codes: 1sh5 1sh6
15274920 M.G.Klein, W.Shi, U.Ramagopal, Y.Tseng, D.Wirtz, D.R.Kovar, C.J.Staiger, and S.C.Almo (2004).
Structure of the actin crosslinking core of fimbrin.
  Structure, 12, 999.
PDB codes: 1pxy 1rt8
15548864 W.Lehman, R.Craig, J.Kendrick-Jones, and A.J.Sutherland-Smith (2004).
An open or closed case for the conformation of calponin homology domains on F-actin?
  J Muscle Res Cell Motil, 25, 351-358.  
12657793 F.Ekström, G.Stier, and U.H.Sauer (2003).
Crystallization of the actin-binding domain of human alpha-actinin: analysis of microcrystals of SeMet-labelled protein.
  Acta Crystallogr D Biol Crystallogr, 59, 724-726.  
14517317 S.H.Litjens, J.Koster, I.Kuikman, S.van Wilpe, J.M.de Pereda, and A.Sonnenberg (2003).
Specificity of binding of the plectin actin-binding domain to beta4 integrin.
  Mol Biol Cell, 14, 4039-4050.  
12517699 S.J.Winder (2003).
Structural insights into actin-binding, branching and bundling proteins.
  Curr Opin Cell Biol, 15, 14-22.  
12612583 S.P.Robertson, S.R.Twigg, A.J.Sutherland-Smith, V.Biancalana, R.J.Gorlin, D.Horn, S.J.Kenwrick, C.A.Kim, E.Morava, R.Newbury-Ecob, K.H.Orstavik, O.W.Quarrell, C.E.Schwartz, D.J.Shears, M.Suri, J.Kendrick-Jones, and A.O.Wilkie (2003).
Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans.
  Nat Genet, 33, 487-491.  
12716899 T.S.Fraley, T.C.Tran, A.M.Corgan, C.A.Nash, J.Hao, D.R.Critchley, and J.A.Greenwood (2003).
Phosphoinositide binding inhibits alpha-actinin bundling activity.
  J Biol Chem, 278, 24039-24045.  
11879882 A.E.Emery (2002).
The muscular dystrophies.
  Lancet, 359, 687-695.  
12237450 M.Novatchkova, and F.Eisenhaber (2002).
A CH domain-containing N terminus in NuMA?
  Protein Sci, 11, 2281-2284.  
11259305 A.Orlova, I.N.Rybakova, E.Prochniewicz, D.D.Thomas, J.M.Ervasti, and E.H.Egelman (2001).
Binding of dystrophin's tandem calponin homology domain to F-actin is modulated by actin's structure.
  Biophys J, 80, 1926-1931.  
11336782 A.van der Flier, and A.Sonnenberg (2001).
Structural and functional aspects of filamins.
  Biochim Biophys Acta, 1538, 99.  
11381081 N.Volkmann, D.DeRosier, P.Matsudaira, and D.Hanein (2001).
An atomic model of actin filaments cross-linked by fimbrin and its implications for bundle assembly and function.
  J Cell Biol, 153, 947-956.  
  11305946 R.G.Roberts (2001).
Dystrophins and dystrobrevins.
  Genome Biol, 2, REVIEWS3006.  
11166570 S.J.Winder (2001).
The complexities of dystroglycan.
  Trends Biochem Sci, 26, 118-124.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.

 

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