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PDBsum entry 1dxx
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Structural protein
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PDB id
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1dxx
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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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.
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Authors
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F.L.Norwood,
A.J.Sutherland-Smith,
N.H.Keep,
J.Kendrick-Jones.
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Ref.
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Structure, 2000,
8,
481-491.
[DOI no: ]
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PubMed id
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Abstract
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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.
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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.
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The above figure is
reprinted
by permission from Cell Press:
Structure
(2000,
8,
481-491)
copyright 2000.
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