Spectrin

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A schematic diagram of spectrin and other cytoskeletal molecules Cytoskeleton (Elliptocytosis).png
A schematic diagram of spectrin and other cytoskeletal molecules
Localization of alpha-II spectrin in green under the plasma membrane of rat neurons in tissue culture as shown with confocal microscopy and immunofluorescence. The nuclei of the cells is revealed in blue by the DNA dye DAPI. Spectrin localization under the neuronal plasme membrane..jpg
Localization of alpha-II spectrin in green under the plasma membrane of rat neurons in tissue culture as shown with confocal microscopy and immunofluorescence. The nuclei of the cells is revealed in blue by the DNA dye DAPI.

Spectrin is a cytoskeletal protein that lines the intracellular side of the plasma membrane in eukaryotic cells. Spectrin forms pentagonal or hexagonal arrangements, forming a scaffold and playing an important role in maintenance of plasma membrane integrity and cytoskeletal structure. [1] The hexagonal arrangements are formed by tetramers of spectrin subunits 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. The protein is named spectrin since it was first isolated as a major protein component of human red blood cells which had been treated with mild detergents; the detergents lysed the cells and the hemoglobin and other cytoplasmic components were washed out. In the light microscope the basic shape of the red blood cell could still be seen as the spectrin-containing submembranous cytoskeleton preserved the shape of the cell in outline. This became known as a red blood cell "ghost" (spectre), and so the major protein of the ghost was named spectrin.

Contents

In certain types of brain injury such as diffuse axonal injury, spectrin is irreversibly cleaved by the proteolytic enzyme calpain, destroying the cytoskeleton. [2] Spectrin cleavage causes the membrane to form blebs and ultimately to be degraded, usually leading to the death of the cell. [3] Spectrin subunits may also be cleaved by caspase family enzymes, and calpain and caspase produce different spectrin breakdown products which can be detected by western blotting with appropriate antibodies. Calpain cleavage may indicate activation of necrosis, while caspase cleavage may indicate apoptosis. [4]

In erythrocytes

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.

In humans, association with the intracellular face of the plasma membrane is by indirect interaction, through direct interactions with protein 4.1 and ankyrin, with the transmembrane ion transporter band 3 Protein 4.2 binds the spectrin tail region to the transmembrane protein glycophorin A. [5] 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 rarely hereditary spherocytosis. [6]

In invertebrates

There are three spectrins in invertebrates, α,β and βH. Mutations in βH spectrin in C. elegans cause defects in morphogenesis resulting in a significantly shorter, but otherwise mostly normal, animal that moves and reproduces. These animals are called "sma" for their small phenotype and carry mutations in the C. elegans sma-1 gene. [7] 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. [8] 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. [9] In animals, spectrin forms the meshwork that provides red blood cells their shape.

In vertebrates

Vertebrate spectrin genes

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.

Role in muscle tissue

Some evidence for the role of spectrins in muscle tissues exist. In myocardial cells, aII spectrin distribution is coincident with Z-discs and the plasma membrane of myofibrils. [10] 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.

See also

Related Research Articles

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<span class="mw-page-title-main">Actin</span> Family of proteins

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<span class="mw-page-title-main">Hereditary spherocytosis</span> Medical condition

Hereditary spherocytosis (HS) is a congenital hemolytic disorder, wherein a genetic mutation coding for a structural membrane protein phenotype leads to a spherical shaping of erythrocytic cellular morphology. As erythrocytes are sphere-shaped (spherocytosis), rather than the normal biconcave disk-shaped, their morphology interferes with these cells' abilities to be flexible during circulation throughout the entirety of the body – arteries, arterioles, capillaries, venules, veins, and organs. This difference in shape also makes the red blood cells more prone to rupture under osmotic stress, mechanical stress, or both. Cells with these dysfunctional proteins are degraded in the spleen, which leads to a shortage of erythrocytes resulting in hemolytic anemia.

<span class="mw-page-title-main">Node of Ranvier</span> Gaps between myelin sheaths on the axon of a neuron

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<span class="mw-page-title-main">Calpain</span> Protease enzyme present in mammals and other organisms

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<span class="mw-page-title-main">Hereditary elliptocytosis</span> Medical condition

Hereditary elliptocytosis, also known as ovalocytosis, is an inherited blood disorder in which an abnormally large number of the person's red blood cells are elliptical rather than the typical biconcave disc shape. Such morphologically distinctive erythrocytes are sometimes referred to as elliptocytes or ovalocytes. It is one of many red-cell membrane defects. In its severe forms, this disorder predisposes to haemolytic anaemia. Although pathological in humans, elliptocytosis is normal in camelids.

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<span class="mw-page-title-main">Ankyrin</span> Protein family

Ankyrins are a family of proteins that mediate the attachment of integral membrane proteins to the spectrin-actin based membrane cytoskeleton. Ankyrins have binding sites for the beta subunit of spectrin and at least 12 families of integral membrane proteins. This linkage is required to maintain the integrity of the plasma membranes and to anchor specific ion channels, ion exchangers and ion transporters in the plasma membrane. The name is derived from the Greek word ἄγκυρα (ankyra) for "anchor".

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Protein 4.1,, is a protein associated with the cytoskeleton that in humans is encoded by the EPB41 gene. Protein 4.1 is a major structural element of the erythrocyte membrane skeleton. It plays a key role in regulating membrane physical properties of mechanical stability and deformability by stabilizing spectrin-actin interaction. Protein 4.1 interacts with spectrin and short actin filaments to form the erythrocyte membrane skeleton. Mutations of spectrin and protein 4.1 are associated with elliptocytosis or spherocytosis and anemia of varying severity.

<span class="mw-page-title-main">Spectrin, alpha 1</span> Protein-coding gene in the species Homo sapiens

Spectrin alpha chain, erythrocyte is a protein that in humans is encoded by the SPTA1 gene.

<span class="mw-page-title-main">SPTAN1</span> Protein-coding gene in the species Homo sapiens

Alpha II-spectrin, also known as Spectrin alpha chain, brain is a protein that in humans is encoded by the SPTAN1 gene. Alpha II-spectrin is expressed in a variety of tissues, and is highly expressed in cardiac muscle at Z-disc structures, costameres and at the sarcolemma membrane. Mutations in alpha II-spectrin have been associated with early infantile epileptic encephalopathy-5, and alpha II-spectrin may be a valuable biomarker for Guillain–Barré syndrome and infantile congenital heart disease.

<span class="mw-page-title-main">SPTBN1</span> Protein-coding gene in the species Homo sapiens

Spectrin beta chain, brain 1 is a protein that in humans is encoded by the SPTBN1 gene.

<span class="mw-page-title-main">SPTBN4</span> Protein-coding gene in the species Homo sapiens

Spectrin, beta, non-erythrocytic 4, also known as SPTBN4, is a protein that in humans is encoded by the SPTBN4 gene.

<span class="mw-page-title-main">Ankyrin-1</span> Protein-coding gene in the species Homo sapiens

Ankyrin 1, also known as ANK-1, and erythrocyte ankyrin, is a protein that in humans is encoded by the ANK1 gene.

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<span class="mw-page-title-main">Neurotubule</span>

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References

  1. ↑ Huh, Gi-Yeong; Glantz, Susan B.; Je, Soojung; Morrow, Jon S.; Kim, Jung H. (December 2001). "Calpain proteolysis of alpha-II-spectrin in the normal adult human brain". Neurosci. Lett. 316 (1): 41–4. doi:10.1016/S0304-3940(01)02371-0. PMID   11720774.
  2. ↑ Büki, A.; Okonkwo, D. O.; Wang, K. K.; Povlishock, J. T. (April 2000). "Cytochrome c release and caspase activation in traumatic axonal injury". J. Neurosci. 20 (8): 2825–34. doi: 10.1523/JNEUROSCI.20-08-02825.2000 . PMC   6772193 . PMID   10751434.
  3. ↑ Castillo, MR; Babson, JR. (1998). "Ca2+-dependent mechanisms of cell injury in cultured cortical neurons". Neuroscience. 86 (4): 1133–1144. doi:10.1016/S0306-4522(98)00070-0. PMID   9697120.
  4. ↑ Li, Jia; Li, Xue-Yuan; Feng, Dong-Fu; Pan, Dong-Chao (December 2010). "Biomarkers associated with diffuse traumatic axonal injury: exploring pathogenesis, early diagnosis, and prognosis". J. Trauma. 69 (6): 1610–1618. doi:10.1097/TA.0b013e3181f5a9ed. PMID   21150538.
  5. ↑ Pathologic Basis of Disease, 8th edition Robbins and Cotran (2010) page 642
  6. ↑ Delaunay, J (1995). "Genetic disorders of the red cell membranes". FEBS Letters. 369 (1): 34–37. doi: 10.1016/0014-5793(95)00460-Q . PMID   7641880.
  7. ↑ McKeown, C; Praitis VM; Austin JA (1998). "sma-1 encodes a betaH-spectrin homolog required for Caenorhabditis elegans morphogenesis". Development. 125 (11): 2087–98. PMID   9570773.
  8. ↑ Hammarlund, M; Davis WS; Jorgensen EM (2000). "Mutations in β-Spectrin Disrupt Axon Outgrowth and Sarcomere Structure". Journal of Cell Biology. 149 (4): 931–942. doi:10.1083/jcb.149.4.931. PMC   2174563 . PMID   10811832.
  9. ↑ Featherstone, DE; Davis WS; Dubreuil RR; Broadie K (2001). "Drosophila alpha- and beta-spectrin mutations disrupt presynaptic neurotransmitter release". Journal of Neuroscience. 21 (12): 4215–4224. doi: 10.1523/JNEUROSCI.21-12-04215.2001 . PMC   6762771 . PMID   11404407 . Retrieved 2007-02-11.
  10. ↑ Bennett, PM; Baines AJ; Lecomte MC; Maggs AM; Pinder JC (2004). "Not just a plasma membrane protein: in cardiac muscle cells alpha-II spectrin also shows a close association with myofibrils". Journal of Muscle Research and Cell Motility. 25 (2): 119–126. doi:10.1023/B:JURE.0000035892.77399.51. PMID   15360127.
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