Dystrophin and Associated Muscle Proteins

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Dystrophin and Associated Muscle Proteins
Kevin Cashman Biol. 317 March 22, 2006
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Dystrophin

• A 427-kDa cytoskeletal protein and a member of
  the ß-spectrin/a-actinin protein family
• Has an actin binding domain to bind to F-actin
  myofilaments
• Gene contains 79 exons in which with a high
  rate of alternate splicing on the C-terminus
• Associates with many other proteins to form the
  dystrophin glyco-protein complex (DGC)

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List of Dystrophin Associated Proteins

• ß-dystroglycan sacrolemma spanning protein
  that dystrophin binds to
• F-actin N-terminus of dystrophin binds to
• ß-dystrobrevin sacroplasmic protein that binds
  to dystrophin and the sarcoglycan complex
• Sarcoglycan complex a,ß,?,d-sarcoglycan
  proteins embedded into the sarcolemma that
  associates with ß-dystrobrevin, and a and
  ß-dystroglycan primarily.

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List of Dystrophin Associated Proteins (cont.)

• a-dystroglycan associates to ß-dystroglycan
  and laminin-2 outside of the sacrolemma
• laminin-2 binds to the extracellular matrix
  and accociates with a-dystroglycan

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Functions of DGC

• Two functions
• To act as a shock-like complex to protect the
  muscle fibers sacrolemma from stress induced
  fractures during muscle contractions
• Associated proteins, nitric oxide synthase
  (NOS) and growth factor receptor bound protein 2
  (GRB2), maintain cell viability and regulate the
  functions of the cytoskeleton.

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Problems

• Mutations in the dystrophin gene can cause
  truncated proteins that get low productions
  levels, or the dystrophin protein isnt produced
  at all. Without this the complex cannot bind to
  F-actin and fulfill its role.
• There are hundreds of mutations associated with
  the dystrophin gene in the majority of the exons
  and many of the mutations cause a type of
  dystrophy.
• Duchenne muscular dystrophy (absent) and Becker
  muscular dystrophy (truncated) are two of the
  most severe mutations.

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References

• The Dystrophin Story, http//compbio.berkeley.ed
  u/people/ed/rust/Dystrophin.html
• Function and Genetics of Dystrophin and
  Dystrophin-Related Proteins in Muscle, Blake et
  al (2002) Physiological Reviews, 82 291-329.
• http//www.mja.com.au/public/issues/179_09_03110
  3/byr10494_fm-1.gif
• http//images.google.com/imgres?imgurlhttp//embr
  yology.med.unsw.edu.au/DNA/images/dystrophin.gifi
  mgrefurlhttp//embryology.med.unsw.edu.au/DNA/SWI
  SS-PROTdystrophin.htmh224w207sz13tbnidbIU8
  EqiYBpH9nMtbnh102tbnw94hlenstart5prev/i
  mages3Fq3DDystrophin26svnum3D1026hl3Den26lr
  3D
• An Introduction to Human Molecular Genetics
  (2005), Jack Pasternak Miley-Liss Inc., New
  Jersey.