Structure of the utrophin actin-binding domain bound to F-actin reveals binding by an induced fit mechanism.
Utrophin is a large ubiquitously expressed cytoskeletal protein, homologous to dystrophin, the protein disrupted in Duchenne muscular dystrophy. The association of both proteins with the actin cytoskeleton is functionally important and is mediated by a domain at their N termini, conserved in members of the spectrin superfamily, including alpha-actinin, beta-spectrin and fimbrin. We present the structure of the actin-binding domain of utrophin in complex with F-actin, determined by cryo-electron microscopy and helical reconstruction, and a pseudo-atomic model of the complex, generated by docking the crystal structures of the utrophin domain and F-actin into the reconstruction. In contrast to the model of actin binding proposed for fimbrin, the utrophin actin-binding domain appears to associate with actin in an extended conformation. This conformation places residues that are highly conserved in utrophin and other members of the spectrin superfamily at the utrophin interface with actin, confirming the likelihood of this binding orientation. This model emphasises the importance of protein flexibility in modeling interactions and presents the fascinating possibility of a diversity of actin-binding mechanisms among related proteins.
Moores
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CA
MRC Laboratory of Molecular Biology, Hills Road, Cambridge, CB2 2QH, UK.
Keep
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NH
Kendrick-Jones
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J
D000199:Actins / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure*; D000495:Allosteric Site; D000595:Amino Acid Sequence; D001704:Biopolymers / Q000737:chemistry / Q000378:metabolism; D017124:Conserved Sequence; D020285:Cryoelectron Microscopy; D003460:Crystallization; D003598:Cytoskeletal Proteins / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure*; D019281:Dimerization; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D018583:Pliability; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D049411:Utrophin
D000199:Actins; D001704:Biopolymers; D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; D049411:Utrophin