Spectrin tetramer

What is the function of the membrane skeleton There is a group of hereditary diseases including spherocytosis in which erythrocytes do not maintain their biconcave disc shape but become spherical or have other abnormal shapes and are extremely fragile.269 272 Causes of spherocytosis include defective formation of spectrin tetramers and defective association of spectrin with ankyrin or the band 4.1 protein.265 273 Thus, the principal functions of these proteins in erythrocytes may be to strengthen the membrane and to preserve the characteristic shape of erythrocytes during their 120-day lifetime in the bloodstream. In other cells the spectrins are able to interact with microtubules, which are absent from erythrocytes, and to microtubule-associated proteins of the cytoskeleton (Chapter 7, Section F).270 In nerve terminals a protein similar to erythrocyte protein 4.1 may be involved in transmitter release.274 The cytoskeleton is also actively involved in transmembrane signaling. 

The structure of spectrin and the location of spectrin in the cytoskeleton. (a) An a/3 dimer of spectrin. Both a and f3 subunits are extended structures consisting of end-to-end domains of 106 amino-acyl residues folded into three a helices the subunits twist about one another loosely as shown. (b) The erythrocyte membrane skeleton. Spectrin tetramers ((X2P2), shown in yellow, are linked to the cytoplasmic domain of the anion channel (blue) by the protein ankyrin (red), and to glycophorin and actin filaments by protein 4.1. This structure lends stability to the red cell membrane while maintaining sufficient flexibility to allow erythrocytes to withstand substantial shear forces in the peripheral circulation. 

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.

N-terminal actin-binding domains and in the spectrin repeats that form the rod domains (Davison and Critchley, 1988). The spectrin repeats are found in distinct multiples in each protein, resulting in a characteristic actin crosslinking distance. a-Actinin contains four repeats, /3-spectrin contains 17, a-spectrin contains 20, and dystrophin contains 24. The sequences of some spectrin repeats of a- and /3-spectrin are similar in many ways to the four repeats present in a-actinin (Dubreuil, 1991). Within the cell, a-actinin and spectrin dimerize, although the spectrins interact further to generate a functional tetramer (Fig. 1). Most notable is that the ends of the native spectrin tetramer involved in the dimerization event show remarkable similarity to the rod domain repeats of a-actinin that also mediate dimer formation. 

In erythrocytes and most other cells, the major structural link of plasma membranes to the cytoskeleton is mediated by interactions between ankyrin and various integral membrane proteins, including Cf/HCOj antiporters, sodium ion pumps and voltage-dependent sodium ion channels. Ankyrin also binds to the =100 nm, rod-shaped, antiparallel a(3 heterodimers of spectrin and thus secures the cytoskeleton to the plasma membrane. Spectrin dimers self-associate to form tetramers and further to form a polygonal network parallel to the plasma membrane (Fig. 2-9D). Neurons contain both spectrin I, also termed erythroid spectrin, and spectrin II, also termed fodrin. Spectrin II is found throughout neurons, including axons, and binds to microtubules, whereas spectrin I occurs only in the soma and dendrites. 

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 major components of the membrane skeleton are spectrin, actin, and protein 4.1. Spectrin is a highly flexible, rodlike molecule composed of two nonidentical polypeptides a-spectrin and (3-spectrin.These chains are aligned side by side in the form of a a(3-heterodimer, and spectrin heterodimers in turn join head to head to form (aP)2-tetramers. The tail ends of spec-... 

The head of each spectrin chain interacts with the head of the complementary chain of another heterodimer. In the tetramer, there are paired interactions (Fig. 5-31), while in higher oligomers, a closed loop is formed, as the head region is quite flexible. This is shown for the hexamer in Fig. 5-39, but this self-association may continue indefinitely. 

The hexagonal arrangements are formed by tetramers of spectrin associating with short actin filaments at either end of the tetramer. These short actin filaments act as junctional complexes, allowing the formation of the hexagonal mesh. 

Spectrin - elongated molecules made up of 012/ 2 tetramers. The tetramers form a chainlike structure that links the many components of the ghost and the skeleton. Spectrins contain a large portion of their structure in the form of an oi-helix and appear to be linked at their ends through short chains of actin molecules, together with band 4.1 protein and adducin. 

Spectrin is a peripheral membrane protein of erythrocytes. It contains two copies each of an ot and a subunit, forming a tetramer. Spectrin acts like a fiber, linking together the various components of the erythrocyte membrane skeleton (Figure 10.18). 

Other experiments with erythrocytes also confirm the interaction of protein and lipids. In patients with hereditary pyropoikilocytosis the spectrin dimers cannot associate into the normal tetramers and this gives rise to enhanced thermosensitivity of the cytoskeleton. The cells also have an... 

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