Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026850 (muscular dystrophy)
 5,870 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dystrophin links the actin cytoskeleton to the dystroglycan complex in the plasma membrane as part of the linkage between the cytoskeleton and the extracellular matrix. Damage to or absence of dystrophin causes Duchenne or Becker muscular dystrophy. It has been proposed that elevating the levels of utrophin, a close homologue of dystrophin, may act as a therapy for these forms of muscular dystrophy. This requires that there is a close functional equivalence of these two proteins. In both utrophin and dystrophin, the main actin-binding region is at the N terminus. It is related to sequences found in a number of other proteins including alpha-actinin, spectrin and fimbrin. Recent structural and biochemical studies of these proteins have shown that although the method of binding to actin is broadly similar, there are significant differences. There are even differences between utrophin and dystrophin. These studies imply that some caution should be applied to claims that utrophin and dystrophin are completely functionally interchangeable. In this paper, I review studies that elucidate and compare the actin-binding function of utrophin and dystrophin, particularly those initiated in the laboratory of Dr. John Kendrick-Jones at the MRC in Cambridge.
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PMID:Structural comparison of actin binding in utrophin and dystrophin. 1138 92

Dystrophin is a long, rod-shaped cytoskeleton protein implicated in muscular dystrophy (MDys). Utrophin is the closest autosomal homolog of dystrophin. Both proteins have N-terminal actin-binding domain (N-ABD), a central rod domain and C-terminal region. N-ABD, composed of two calponin homology (CH) subdomains joined by a helical linker, harbors a few disease causing missense mutations. Although the two proteins share considerable homology (>72%) in N-ABD, recent structural and biochemical studies have shown that there are significant differences (including stability, mode of actin-binding) and their functions are not completely interchangeable. In this investigation, we have used extensive molecular dynamics simulations to understand the differences and the similarities of these two proteins, along with another actin-binding protein, fimbrin. In silico mutations were performed to identify two key residues that might be responsible for the dynamical difference between the molecules. Simulation points to the inherent flexibility of the linker region, which adapts different conformations in the wild type dystrophin. Mutations T220V and G130D in dystrophin constrain the flexibility of the central helical region, while in the two known disease-causing mutants, K18N and L54R, the helicity of the region is compromised. Phylogenetic tree and sequence analysis revealed that dystrophin and utrophin genes have probably originated from the same ancestor. The investigation would provide insight into the functional diversity of two closely related proteins and fimbrin, and contribute to our understanding of the mechanism of MDys.
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PMID:Flexibility in the N-terminal actin-binding domain: clues from in silico mutations and molecular dynamics. 2562 4