Crystal structure of the actin-binding region of utrophin reveals a head-to-tail dimer

Background: Utrophin is a large multidomain protein that belongs to a super family of actin-binding proteins, which includes dystrophin, alpha-actinin, beta-spectrin, fimbrin, filamin and plectin. All the members of this famil y contain a common actin-binding region at their N termini and perform a wi de variety of roles associated with the actin cytoskeleton. Utrophin is the autosomal homologue of dystrophin, the protein defective in the X-linked D uchenne and Becker muscular dystrophies, and upregulation of utrophin has b een suggested as a potential therapy for muscular dystrophy patients. Results: The structure of the actin-binding region of utrophin, consisting of two calponin-homology (CH) domains, has been solved at 3.0 Angstrom reso lution. It is composed of an antiparallel dimer with each of the monomers b eing present in an extended dumbell shape and the two CH domains being sepa rated by a long central helix. This extended conformation is in sharp contr ast to the compact monomer structure of the N-terminal actin-binding region of fimbrin. Conclusions: The crystal structure of the actin-binding region of utrophin suggests that these actin-binding domains may be more flexible than was pre viously thought and that this flexibility may allow domain reorganisation a nd play a role in the actin-binding mechanism. Thus utrophin could possibly bind to actin in an extended conformation so that the sites previously ide ntified as being important for actin binding may be directly involved in th is interaction.