Dystrophin structural domains

The function of spectrin superfamily proteins is particularly evident when taken in context of their cellular localization. They often form flexible links or structures that allow interactions with the cellular cyto-skeletal architecture and the membrane. In both spectrin and dystrophin, such a function is performed, but the spectrin repeats of these molecules are also able to interact with actin and contribute to binding. A portion of the dystrophin rod domain that spans residues 11-17 contains a number of basic repeats that allow a lateral interaction with filamentous actin (Rybakova et al., 2002). The homologous utrophin can also interact laterally with actin. This interaction is distinct from that of dystrophin, as the utrophin rod domain lacks the basic repeat cluster and associates with actin via the first ten spectrin repeats (Rybakova et al., 2002). /3-Spectrin also exhibits an extended contact with actin via the first spectrin repeat. In this situation, it was found that the extended contact increased the association of the adjacent ABD with actin (Li and Bennett, 1996). In conjunction with this interaction, it has been found that the second repeat is also required for maximal interaction with adducin (Li and Bennett, 1996), a protein localized at the spectrin-actin junction that is believed to contribute to the assembly of this structure in the membrane skeletal network (Gardner and Bennett, 1987). In the erythrocyte cytoskeletal lattice, /3-spectrin interacts with ankyrin, which in turn binds to the cytoplasmic domain of the membrane-associated anion exchanger. This indirect link to the cellular membrane occurs via repeat 15 of /3-spectrin (Kennedy et al., 1991) and is largely responsible for the attachment of the spectrin-actin network to the erythrocyte membrane (reviewed in Bennett and Baines, 2001). A much larger number of direct links to transmembrane proteins have been determined for the spectrin repeats of o-actinin (reviewed in Djinovic-Carugo et al, 2002). 

The cortical region of many cells is enriched in actin and associated actin-binding proteins, which function in motility, cell shape maintenance, and membrane protein distribution in polarized cells. In some cases, discrete structures anchor actin to the membrane, as is the case for intercellular adherens junctions and cell-substrate focal contacts. In certain special cell types, the fundamental blueprint for an adherens junction is taken to a new structural level, serving as scaffolding for cell-type specific complexes, such as the dystrophin-associated protein complex (DPC) in striated muscle. Although for years morphological studies have described a close association with IF with the actin-rich cortex, recent advances in methods to study protein-protein interactions have provided new insight into the intimate structural and functional relationship between IFs and these membrane domains. 

Fig. 1. Structure of spectrin superfamily proteins. Modular domains within each protein are clearly defined. Shaded spectrin repeats represent coiled coils involved in dimerization events incomplete repeats represent proportionally the number of coiled-coil helices contributed by a- and /3-spectrin when generating a complete spectrin repeat during formation of the spectrin tetramer. The dashed lines indicate how two spectrin heterodimers interact to form a functional spectrin tetramer. Asterisks in the dystrophin spectrin repeats represent the position of the two greater repeats in dystrophin with respect to utrophin, which in all other respects has a similar overall structure. Numbers in the EF hand regions represent the number of EF hand motifs.

The actin-binding domains (ABD) of spectrin, o-actinin, and dystrophin consist of approximately 240 residues that comprise two functionally distinct but structurally equivalent domains (Gimona and Winder, 1998 ... 

As mentioned above, the WW domain is another example of a protein-protein interaction module that binds proline-rich sequences (Kay et al., 2000). Dystrophin and utrophin WW domains interact predominantly with the extracellular matrix receptor dystroglycan, which contains a type 1 WW motif of consensus PPxY (reviewed in Ilsley et al., 2002 Winder, 2001). A structure of a WW domain from dystrophin was solved recently as part of a structure including the EF-hand region, and also with and without a bound /3-dystroglycan peptide (Huang et al., 2000). 

Keep, N. H., Norwood, F. L., Moores, C. A., Winder, S. J., and Kendrick-Jones, J. (1999a). The 2.0A structure of the second calponin homology domain from the actin-binding region of the dystrophin homologue utrophin./ Mol. Biol. 285, 1257-1264. 

Norwood, F. L., Sutherland-Smith, A. J., Keep, N. H., and Kendrickjones, J. (2000). The structure of the N-terminal ac tin-binding domain of human dystrophin and how mutations in this domain may cause Duchenne or Becker muscular dystrophy. Structure Fold Des. 8, 481—491. 

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