Cytoskeleton spectrin

Protein 4.1, a globular protein, binds tightly to the tail end of spectrin, near the actin-binding site of the latter, and thus is part of a protein 4.1-spectrin-actin ternary complex. Protein 4.1 also binds to the integral proteins, glycophorins A and C, thereby attaching the ternary complex to the membrane. In addition, protein 4.1 may interact with certain membrane phospholipids, thus connecting the lipid bilayer to the cytoskeleton. 

Mechanical functions of cells require interactions between integral membrane proteins and the cytoskeleton 29 The spectrin-ankyrin network comprises a general form of membrane-organizing cytoskeleton within which a variety of membrane-cytoskeletal specializations are interspersed 29 Interaction of rafts with cytoskeleton is suggested by the results of video microscopy 29... 

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. 

Cross-link MFs in membrane cytoskeleton Links MF/spectrin to membrane proteins... 

Holleran, E. A. and Holzbaur, E. L. Speculating about spectrin new insights into the Golgi-associated cytoskeleton. Trends Cell Biol. 8 26-29,1998. 

Spectrin/fodrin Actin crosslinking protein in cortical cytoskeleton (Wl)... 

A primary function of the SH3 domains is to form fimctional oligomeric complexes at defined subcellular sites, frequently in cooperation with other modular domains. SH3 domains are foimd in many proteins associated with the cytoskeleton or with the plasma membrane. Examples are the actin binding protein a-spectrin and myosin lb. Furthermore, SH3 interactions are involved in signal transduction in the Ras pathway (see Chapter 9). 

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. 

One of the major integral proteins of the erythrocyte membrane is the anion channel, or band-3 protein, which moves Cl- and HC03 anions across the membrane. The anion transporter has two identical subunits with molecular weights of about 95,000, and each subunit probably has 10 or 11 transmembrane helices. The band-3 protein is attached to the spectrin cytoskeleton through a smaller protein, anky-rin. The cytosolic domain of the anion transporter also binds the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase. 

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. 

Spectrin is a common component of the submembranous cytoskeleton. It was first identified as a major constituent of the erythrocyte membrane cytoskeleton, but has since been found in many other vertebrate tissues as well as in the nonvertebrates Drosophila, Acanthamoeba, Dictyostelium, and echinoderms (Bennett and Condeelis, 1988 Byers et al., 1992 Dubreuil et al., 1989 Pollard, 1984 Wessel and Chen., 1993). The ease with which spectrin could be isolated from erythrocyte ghosts made it an ideal candidate for the study of the biochemical processes involved in the assembly and organization of the cytoskeleton (Gratzer, 1985). 

Proteomic studies have revealed additional FRAPs that are not PDZ proteins (17,24,29). Examples of these FRAPs include components of the actin-spectrin cytoskeleton (e.g., beta-actin, spectrin alpha II chain) and the intracellular signaling apparatus (e.g., calmodulin, and protein kinase C [PKC]0-interacting protein). 

In addition to organelles, the cell cytoplasm contains actin filaments that make up the cellular cytoskeleton that controls shape. Myosin and a-actinin are also found in the cytoplasm and are believed to be involved in cell contraction. Other filaments including intermediate filaments, tubulin, calmodulin, and spectrin form networks within the cytoplasm that modify cell and organelle mobility and shape. 

In certain types of brain injury, such as diffuse axonal injury, spectrin is irreversibly cleaved by the proteolytic enzyme calpain. This destroys the cytosketelon, causing the membrane to form blebs, irregular bulges in the plasma membrane of a cell caused by localised decoupling of the cytoskeleton from the plasma membrane, ultimately leading to degradation and usually death of the cell. 

Ogawa Y, Schafer DP, Horresh 1, Bar V, Hales K, Yang Y, Susuki K, Peles E, Stankewich MC, Rasband MN (2006) Spectrins and ankyrinB constitute a specialized paranodal cytoskeleton. J Neurosd 26 5230-5239... 

Accumulating evidence clearly points at involvement of the cell cytoskeleton in the compartmentalization of the membrane, in particular, the fine cytoskeleton filaments formed by actin in most eukaryotic cells or spectrin in mammalian red blood cells. However, single-particle tracking experiments show the same patterns of hop-diffusion for lipid molecules located in the extracellular leaflet of the plasma membrane. How can the membrane skeleton, which is located only on the cytoplasmic surface of the membrane, suppress the motion of lipids on the extracellular side ... 

Cell death due to apoptosis or necrosis is not the only form of tubular injury in AKI. There is also sub-lethal injury causing cell dysfunction. For example, alterations in proximal tubular cell polarity occur during renal ischemia. Tubule polarity is essential for its primary function of selective reabsorption of ions from the tubular fluid. Sodium-potassium-ATPase (NaK-ATPase), the enzyme, normally localized to the basolateral membrane, maintains tubular polarity by regulation of cellular transport sodium and potassium in proximal tubules. NaK-ATPase is hnked to the cytoskeleton/ membrane complex by a variety of proteins including spectrin. It has been demonstrated that in early reperfusion period spectrin dissociates from the cytosleleton and NaK-ATPase moves from the basolateral membrane into the cytoplasm and apical membrane [54-58]. 

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