Just a thought on Red Blood Cell rigidity

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Posted by John Walker on May 12, 2001 at 10:52:21:

I'm leaving tonight to show MHK how to cave dive, but wanted to leave you all with this. It off the top of my head, so any mistakes please forgive VBG.

Spectrin is an important protein for maintaining erythrocyte shape. It helps organize integral proteins in the plasma membrane, anchor other important structural proteins to a cytoskeleton, and its interaction with other proteins gives erythrocytes robust deformationproperties that contribute to their long life. In particular, spectrin interacts with various proteins in forming cytoskeleton in a geodesic dome type tropomyomin, and indirectly, actin filiments. The dense meshwork of spectrin forming the skeleton of the flexibility on which the plasma membrane is coupled changes properties under certain strains. Among them , chemical and biochemical perturbation, spectrin beta binding site deformation, temperature perturbation, and osmotic pressure.

Spectrin is an important protein in the cytoplasmic skeleton of cells and it mediates some important structural properties of erythrocytes. Because of its mechanical function, it makes erythrocytes robust in deformation so that they can squeeze through narrow sinusoids in the spleen. In spectrin-deficient cells, this robuust deformability is reduced in deformability towards the shear strenght of the plasma membrane. These spectrin-deficient cells are called spherocytes because the cells lack the central pallor associated with biconcave cells. Thsi sperical or elliptical shape is due to the reduced skeletal rigidity which more uniformly distributes the osmotic pressure over the surface area. Spherocytosis predisposes patients to hemolytic anemias in which red blood cell production in increased to maintain and adequate oxygen carrying capacity of blood.

Some proteins maintian shape even after lipd bilayer dissolve away--suggesting skeleton. This skeleton was found to be microscopically polygonal, with vertices composed of actin. This skeleton is linked to the membrane via ankyrin, a protein which will be discussed shortly. Spectirn occurs in this skeleton in approximently equal proportions to actin. Other important proteins, adducin, tropomyosin, Protein 4.1, Protein 4.2, and beta actin are also important proteins that play a role in the skeleton's organization and regulation of spectrin-actin interactions.

Certain mechanical and structural properties are effected by spectrin. The spectrin skeleton deforms with a shear modulus in proportion to the spectrin density over the surface of the skeleton. It is also noted that integral membrane proteins are not as free to move in cells with spectrin skeletons. These are two hypotheses for why this may be the case: the proteins are simply caught in the network which redices mobility, the integral proteins may be weakly bound to anykin on the spectrin skeleton reducing their rate of movement, end finally, that certain integral proteins are bound to spectrinn and other integral proteins do not move laterally because they are weakly linked to immobile prteins. Spectrin is a flexible protein composed of two subunits, alpha and beta spectrin. These dimers are assembled into tetramers by a weak antiparrallel interaction between alpha and beta, a tight association between antijuxtaposed C terminals of each subunit woith N terminals of its opposite (alpha beta, and beta alpha) subunit. Spectrin can bind to calmodulin via tropomyoson, ankyrin at a beta binding site, and actin crosslinks at the beta subunit. The twisted pair of spectrin subunits may act like a spring, being having more coils per unit distance on the tetramers when compressed, and less coils per unit distance on the tetramers when streches. This may provide some of the robust flexibility the spectrin skeleton enjoys.

At least at nodes of Ranvier, erythocytes, exceptional beta-beta spectrins at neuromuscular juctions, intestinal epithelia, some neurons in brain tissue, and other tissues. This paper focuses on the properties of erythrocyte spectrin because it has been so well documented.

Have high spectrin binding affinities (BENNET 1992) which is important for their intermediate roel as adaptor between spectrin and plasma membrane. Na+/K+ pumps and Na+ channels are integral proteins that co-localize with ankyrin. This co- localization is part of the organization the spectrin cytoskeleton indirectly supports. The N-terminal domains of anykyrins are nearly sperical. The spectrin-binding portion of ankyrins has two subdomains: an acidic, proline rich N terminal, which likely binds the spectrin, and a basic C terminal.

PROTEIN 4.2: interacts with ankyrin and the cytoplasmic and of the erytrocyte. Lack of prtein 4.2 is linked to a decrease in amount of shear force necessary to lyse an erythrocyte.

PROTEIN 4.1: acts on both actin and spectin at lattice points in the skeleton. It is not direct binding to spectrin or actin. The spectrin-actin bons are formed prior to the protein 4.1 development. Spectrin is suggested to form a ternary complex with protien 4.1 because protein 4.1, although equipped with a domain suitable to binding spectrin, this domain is not presented in the configuration that spectrin in observed to interact with protein 4.1. Such ternary complex would be moderately stable if it were shown to occur (Ohannian 1984). Protein 4.1 presents four domains: basic N terminal domain with a Ca++ dependent calmodulin site which may mediate the plasma linkage to protein 4.1, a hydrophilic region, a spectrin-binding region that may act practically independantly of the rest of the molecule which may also be affected by a cAMP dependent protein kinase. Proteon 4.1 also palys a role in integral protein organization on the plasma membrane. Glycophorin C is suggested to be linked or bound to protein 4.1 because cells low in protein 4.1 have subnormal concentrations of Glycophorin C. The cytoplasmic domain of the anion exchanger is also anchored indirectly to the spectrin skeleton by the action of Protein 4.1 and this linkage is dirupted by phosphorylation by kinase C.
(other proteins that may be involve at Spectrin-Actin 4.1 juction:


You'll have to look these up your self or wait until I return from Akumal. My hands are starting to tire.

Spectroin is an important structural and organizational protein which interacts in a completed network of other protiens, namely ankyrin, adducin, ttropomyosin, troopomodulin, protein 4.1, protein 4.2, actin, beta actin, and others. The spectrin skeleton in concert with all of the aforementioned proteins at least partially immobilizes integral proteins on the plasma membrane. Also, the skeleton plays an important role in aking erythrocytes robust because in spectrin-deficient pathologies, the weaker and less shear-resistant plasma membrane loses the characteristic biconcave shape afforted it by the spectrin cytoskeleton, leading to various hemollytic anemias charactorized by elliptical erythrocytes.

John (on his way to Akumal) Walker

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