Spectrins

The leucine zipper DNA-binding proteins, described in Chapter 10, are examples of globular proteins that use coiled coils to form both homo- and heterodimers. A variety of fibrous proteins also have heptad repeats in their sequences and use coiled coils to form oligomers, mainly dimers and trimers. Among these are myosin, fibrinogen, actin cross-linking proteins such as spectrin and dystrophin as well as the intermediate filament proteins keratin, vimentin, desmin, and neurofilament proteins. 

A comparison of the amino acid sequences of dystrophin, a-actinin, and spectrin. The potential hinge segments in die dystrophin structure are indicated. 

FIGURE 17.20 A schematic drawing of the four-helix cluster model for a-actinin and spectrin. Helix 1 is long and is postulated to lie at an angle with respect to the long axis of the repeated domain. 

Davison, M., and Critchley, D., 1988. o -Actinin and the DMD protein contain. spectrin-like repeats. C>//52 159-160. 

Davison, M., et al., 1989. Structural analysis of homologous repeated domains in ct-actinin and. spectrin. International Journal of Biological Macromolecules 11 81—90. 

Myocardial infarcts Ca2+ homeostasis is lost in ischemic areas, triggering inappropriate calpain activity. Desmin and a-spectrin are degraded in ischemic hearts by synthetic calpain inhibitors. Protein and mRNA levels of m and (./-calpain increase after myocardial infarction40-43... 

Multiple sclerosis The 150-kDa calpain specific degradation product of a-spectrin increases 50% in human MS plaques.44 Degradation of the 68-kDa neurofilament protein is inhibited by a synthetic calpain inhibitor45... 

ELF, a (3-Spectrin, is a key component of TGF- 3 signaling that functions to recruit Smads to the receptor by controlling the subcellular localization of Smad 3 and Smad 4. Interestingly, ELF does not appear to interact with SARA or filamin, and in elf mutants, SARA and filamin distribution is the same as in wild-type mice. Thus, TGF- 3 signaling through R-Smad/ ELF interactions may work by way of a different mechanism than that of SARA and filamin. 

Pointed-end-capping proteins are acumentin (65 kD), spectrin (220-260 kD), and p-actinin (37 kD). They also regulate the length of actin filaments. 

Actin is plentiful in the cytoplasm of many animal cells, comprising 5% or more of the total protein present. Four principal patterns of arrangement can be recognized (1) three-dimensional networks of filaments, (2) bundles of parallel filaments with the same polarity, (3) submembranous actin-spectrin (fodrin) networks, and (4) bundles of parallel filaments with alternating polarities. 

Bundles of parallel actin filaments with uniform polarity. The microvilli of intestinal epithelial cells (enterocytes) are packed with actin filaments that are attached to the overlying plasma membrane through a complex composed of a 110-kD protein and calmodulin. The actin filaments are attached to each other through fimbrin (68 kD) and villin (95 kD). The actin bundles that emerge out of the roots of microvilli disperse horizontally to form a filamentous complex, the terminal web, in which several cytoskeletal proteins, spectrin (fodrin), myosin, actinin, and tropomyosin are present. Actin in the terminal web also forms a peripheral ring, which is associated with the plasma membrane on the lateral surfaces of the enterocyte (see Figure 5, p. 24). 

Ankyrin deficiency, amounting to a reduction of approximately 50%, has been found in some patients with the dominant type of HS. A primary defect in ankyrin almost certainly reduces the assembly of spectrin into the membrane skeleton of the red blood cell (Davies and Lux, 1989). 

Proteins closely related to spectrin and ankyrin and many of the associated proteins first identified in erythrocytes also are prevalent in most vertebrate tissues. In these other tissues, spectrin and ankyrin and their associated proteins interact with proteins that may not be expressed in erythrocytes, including ion channel... 

Figured. Diagrammatic representation of the red blood cell cytoskeletal-plasma membrane complex. Spectrin is made up of many homologous triple-helical segments joined by nonhelical regions (Speicher and Marchesi, 1984). Spectrin and actin require accessory proteins to form a membrane-associated network. (This diagram is constructed from data previously published for example, see Stryer, 1988 Davies and Lux, 1989 Bennett and Gilligan, 1993).

Bennett, V. (1989). The spectrin-actin junction of erythrocyte membrane skeletons. Biochim. Biophys. Acta 988, 107-121. 

Bennett, V. Oilligan, D.M. (1993). The spectrin-based membrane skeletal and micron-scale organization of the plasma membrane. Ann. Rev. Cell Biol. 9,27-66. 

Delaunay, J. Dhermy, D. (1993). Mutations involving the spectrin heterodimer contact site Clinical expression and alterations in specific function. Sem. Hematol. 30, 21-33. 

Speicher, D.W. Marchesi, V.T. (1984). Erythrocyte spectrin is comprised of many homologous triple helical segments. Nature 311, 177—180. 

Hereditary spherocytosis (MIM 182900) Mutations in the genes encoding spectrin or other structural proteins in the red cell membrane... 

Hereditary spherocytosis Deficiencies in the amount or in the structure of a or p spectrin, ankyrin, band 3 or band 4.1... 

The major proteins (which include spectrin, ankyrin, the anion exchange protein, actin, and band 4.1) have been studied intensively, and the principal features of their disposition (eg, integral or peripheral), structure, and function have been established. 

The band number refers to the position of migration on SDS-PAGE (see Figure 52-3). The glycophorins are detected by staining with the periodic acid-Schiff reagent. A number of other components (eg, 42 and 4.9) are not listed. Native spectrin is... 

Spectrin, Ankyrin, Other Peripheral Membrane Proteins Help Determine the Shape Flexibility of the Red Blood Cell... 

Ankyrin is a pyramid-shaped protein that binds spectrin. In mrn, ankyrin binds tightly to band 3, securing attachment of spectrin to the membrane. Ankyrin is sensitive to proteolysis, accounting for the appearance of bands 2.2, 2.3, and 2.6, all of which are derived from band 2.1. 

Actin (band 5) exists in red blood cells as short, dou-ble-hehcal filaments of F-actin. The tail end of spectrin dimers binds to actin. Actin also binds to protein 4.1. 

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