Spectrin is a cytoskeletal protein that lines the intracellular side of the plasma membrane of many cell types in pentagonal or hexagonal arrangements, forming a scaffolding and playing an important role in maintenance of plasma membrane integrity and cytoskeletal structure.[1] 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.
In certain types of brain injury such as diffuse axonal injury, spectrin is irreversibly cleaved by the proteolytic enzyme calpain, destroying the cytosketelon.[2] Spectrin cleavage causes the membrane to form blebs and ultimately to be degraded, usually leading to the death of the cell.[3]
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The convenience of using erythrocytes compared to other cell types means they have become the standard model for the investigation of the spectrin cytoskeleton. Dimeric spectrin is formed by the lateral association of αI and βI monomers to form a dimer. Dimers then associate in a head-to-head formation to produce the tetramer. End-to-end association of these tetramers with short actin filaments produces the hexagonal complexes observed.
Association with the intracellular face of the plasma membrane is by indirect interaction, through direct interactions with protein 4.1 and ankyrin, with transmembrane proteins. In animals, spectrin forms the meshwork that provides red blood cells their shape.
The erythrocyte model demonstrates the importance of the spectrin cytoskeleton in that mutations in spectrin commonly cause hereditary defects of the erythrocyte, including hereditary elliptocytosis and hereditary spherocytosis.[4]
There are three spectrins in invertebrates, α,β and βH. A mutation in β spectrin in C. elegans results in an uncoordinated phenotype in which the worms are paralysed and much shorter than wild-type.[5] In addition to the morphological effects, the Unc-70 mutation also produce defective neurons. Neuron numbers are normal but neuronal outgrowth was defective.
Similarly, spectrin plays a role in Drosophila neurons. Knock-out of α or β spectrin in D. melanogaster results in neurons that are morphologically normal but have reduced neurotransmission at the neuromuscular junction.[6] In animals, spectrin forms the meshwork that provides red blood cells their shape.
The spectrin gene family has undergone expansion during evolution. Rather than the one α and two β genes in invertebrates, there are two α spectrins (αI and αII) and five β spectrins (βI to V), named in the order of discovery.
In humans, the genes are:
The production of spectrin is promoted by the transcription factor GATA1.
Some evidence for the role of spectrins in muscle tissues exist. In myocardial cells, αII spectrin distribution is coincident with Z-discs and the plasma membrane of myofibrils.[7] Additionally, mice with an ankyrin (ankB) knock-out have disrupted calcium homeostasis in the myocardia. Affected mice have disrupted z-band and sarcomere morphology. In this experimental model ryanodine and IP3 receptors have abnormal distribution in cultured myocytes. The calcium signaling of the cultured cells is disrupted. In humans, a mutation within the AnkB gene results in the long QT syndrome and sudden death, strengthening the evidence for a role for the spectrin cytoskeleton in excitable tissue.
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