Spectrin superfamily proteins

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.

Within the N-terminal, ABDs of three actin-binding sites (ABS) from spectrin superfamily proteins have been delineated (ABS1, ABS2, and ABS3). The first and third ABS have been localized to the al helix in... 

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). 

Significant contributors to cell structure are those proteins that crosslink actin filaments or connect actin filaments to the cell membrane. Examples of such proteins can be found within the spectrin superfamily of cytoskeletal proteins. This discrete group is principally composed of the actin crosslinking protein o-actinin, and the membrane-associated actin-binding proteins spectrin and dystrophin. 

Fig. 2. Evolution of the spectrin superfamily. Rounded rectangles represent spectrin repeats. Shaded rectangles denote a-actinin-like repeats involved in dimerization, whereas unshaded rectangles represent repeats that were involved in duplication and/ or elongation events. The incomplete spectrin repeats involved in tetramer formation are proportionally represented depending on the number of repeat helices each protein contributes to the formation of a complete spectrin repeat. (Adapted from Dubreuil, 1991 Pascual et al., 1997.) A dystrophin/utrophin ancestor probably diverged from a-actinin at a relatively early stage and then underwent its own series of duplications and acquisitions of new motifs.

The spectrin superfamily is a group of cytoskeletal proteins that have been found to perform a variety of cellular functions. The role of each protein and their interactions within the cellular environment stem from the specific domains found within each protein and the manner in which they are organized. Each of the family members is formed from discrete modular domains that have the ability to interact or modulate specific interactions or impart physical abilities on the protein relevant to its function. The particular members of this protein family have been shown to be evolutionary related. a-Actinin is believed to be the ancestor of the whole group and, indeed, sequence and phylogenetic analysis has found this to be the case. It is astounding that from a simple precursor containing few domains such a family of functionally diverse proteins can be... 

Galkin, V. E., Orlova, A., VanLoock, M. S., Rybakova, I. N., Ervasti, J. M., and Egelman, E. H. (2002). The utrophin actin-binding domain binds F-actin in two different modes Implications for the spectrin superfamily of proteins. / Cell Biol. 157,... 

---