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Trends in Molecular Medicine Jan 2008Ankyrin and spectrin were first discovered as binding partners in the membrane skeleton of human erythrocytes. Mutations in genes encoding these proteins cause... (Review)
Review
Ankyrin and spectrin were first discovered as binding partners in the membrane skeleton of human erythrocytes. Mutations in genes encoding these proteins cause hereditary spherocytosis. Recent advances reveal that ankyrin and spectrin are required for organization of a surprisingly diverse set of proteins, including ion channels and cell adhesion molecules that are localized in specialized membrane domains in many cell types. New insights into the cell biology of ankyrin and spectrin reveal that these proteins actively participate in assembly of specialized membrane domains in addition to their conventional maintenance role as scaffolding proteins. Recently described inherited human diseases due to defects in spectrin or ankyrin include spinocerebellar ataxia type 5 and a cardiac arrhythmia, termed sick sinus syndrome with bradycardia or ankyrin-B syndrome. Together, these studies identify an emerging paradigm for pathogenesis of human disease where failure in cellular localization of membrane-spanning proteins results in loss of physiological function.
Topics: Ankyrins; Genetic Predisposition to Disease; Humans; Membrane Fluidity; Membrane Proteins; Mutation; Spectrin
PubMed: 18083066
DOI: 10.1016/j.molmed.2007.11.005 -
The Journal of Biological Chemistry Jan 2015The dominant paradigm for spectrin function is that (αβ)2-spectrin tetramers or higher order oligomers form membrane-associated two-dimensional networks in association...
The dominant paradigm for spectrin function is that (αβ)2-spectrin tetramers or higher order oligomers form membrane-associated two-dimensional networks in association with F-actin to reinforce the plasma membrane. Tetramerization is an essential event in such structures. We characterize the tetramerization interaction between α-spectrin and β-spectrins in Drosophila. Wild-type α-spectrin binds to both β- and βH-chains with high affinity, resembling other non-erythroid spectrins. However, α-spec(R22S), a tetramerization site mutant homologous to the pathological α-spec(R28S) allele in humans, eliminates detectable binding to β-spectrin and reduces binding to βH-spectrin ∼1000-fold. Even though spectrins are essential proteins, α-spectrin(R22S) rescues α-spectrin mutants to adulthood with only minor phenotypes indicating that tetramerization, and thus conventional network formation, is not the essential function of non-erythroid spectrin. Our data provide the first rigorous test for the general requirement for tetramer-based non-erythroid spectrin networks throughout an organism and find that they have very limited roles, in direct contrast to the current paradigm.
Topics: Actin Cytoskeleton; Actins; Animals; Cell Membrane; Drosophila melanogaster; Humans; Mutation; Protein Multimerization; Spectrin
PubMed: 25381248
DOI: 10.1074/jbc.M114.615427 -
Brain Research Bulletin Jun 1987At least 2 distinct spectrin subtypes, brain spectrin(240/235) and brain spectrin(240/235E), are contained in the mammalian brain. Evidence that these subtypes are... (Review)
Review
At least 2 distinct spectrin subtypes, brain spectrin(240/235) and brain spectrin(240/235E), are contained in the mammalian brain. Evidence that these subtypes are differentially expressed during mouse brain development is reviewed. Brain spectrin(240/235) is detected in fetal brain tissues, and increases 2-fold to adult levels. This subtype is enriched in the cortical cytoplasm of germinative neural cells, and is also associated with fibers resembling axons in the fetus. Brain spectrin(240/235E), a brain subtype specifically detected with antibodies to red blood cell spectrin, is below the limits of detection in the fetal and neonatal brain rapidly increases in concentration during the second postnatal week. Brain spectrin(240/235E) is found in the cell body and dendrites of differentiating neurons and glial cells, but is not expressed in mitotic cells. This subtype is especially prominent in granules cells of the cerebellum and dentate gyrus. The potential function of these spectrin subtypes during neuro-ontogeny is discussed.
Topics: Animals; Brain; Brain Chemistry; Mice; Spectrin
PubMed: 3304546
DOI: 10.1016/0361-9230(87)90219-x -
The Journal of Membrane Biology Dec 1979
Review
Topics: Chemical Phenomena; Chemistry; Erythrocyte Membrane; Erythrocytes; Humans; Lipid Bilayers; Macromolecular Substances; Membrane Proteins; Protein Binding; Protein Conformation; Spectrin
PubMed: 393824
DOI: 10.1007/BF01869164 -
The Journal of Clinical Investigation May 1991
Review
Topics: Animals; Ankyrins; Binding Sites; Blood Proteins; Brain Chemistry; Erythrocytes; Humans; Membrane Proteins; RNA Splicing; Sodium-Potassium-Exchanging ATPase; Spectrin
PubMed: 1850755
DOI: 10.1172/JCI115157 -
The Journal of Neuroscience : the... Nov 2017Axons must withstand mechanical forces, including tension, torsion, and compression. Spectrins and actin form a periodic cytoskeleton proposed to protect axons against...
Axons must withstand mechanical forces, including tension, torsion, and compression. Spectrins and actin form a periodic cytoskeleton proposed to protect axons against these forces. However, because spectrins also participate in assembly of axon initial segments (AISs) and nodes of Ranvier, it is difficult to uncouple their roles in maintaining axon integrity from their functions at AIS and nodes. To overcome this problem and to determine the importance of spectrin cytoskeletons for axon integrity, we generated mice with αII spectrin-deficient peripheral sensory neurons. The axons of these neurons are very long and exposed to the mechanical forces associated with limb movement; most lack an AIS, and some are unmyelinated and have no nodes. We analyzed αII spectrin-deficient mice of both sexes and found that, in myelinated axons, αII spectrin forms a periodic cytoskeleton with βIV and βII spectrin at nodes of Ranvier and paranodes, respectively, but that loss of αII spectrin disrupts this organization. mice have reduced numbers of nodes, disrupted paranodal junctions, and mislocalized Kv1 K channels. We show that the density of nodal βIV spectrin is constant among axons, but the density of nodal αII spectrin increases with axon diameter. Remarkably, mice have intact nociception and small-diameter axons, but severe ataxia due to preferential degeneration of large-diameter myelinated axons. Our results suggest that nodal αII spectrin helps resist the mechanical forces experienced by large-diameter axons, and that αII spectrin-dependent cytoskeletons are also required for assembly of nodes of Ranvier. A periodic axonal cytoskeleton consisting of actin and spectrin has been proposed to help axons resist the mechanical forces to which they are exposed (e.g., compression, torsion, and stretch). However, until now, no vertebrate animal model has tested the requirement of the spectrin cytoskeleton in maintenance of axon integrity. We demonstrate the role of the periodic spectrin-dependent cytoskeleton in axons and show that loss of αII spectrin from PNS axons causes preferential degeneration of large-diameter myelinated axons. We show that nodal αII spectrin is found at greater densities in large-diameter myelinated axons, suggesting that nodes are particularly vulnerable domains requiring a specialized cytoskeleton to protect against axon degeneration.
Topics: Animals; Axons; Cytoskeleton; Demyelinating Diseases; Female; Male; Mice; Mice, Inbred C57BL; Ranvier's Nodes; Spectrin
PubMed: 29038243
DOI: 10.1523/JNEUROSCI.2113-17.2017 -
FEBS Letters Nov 1999In red blood cells, the integrity of the spectrin network is essential for normal cell shape and elasticity. To understand the molecular basis for spectrin's mechanical... (Review)
Review
In red blood cells, the integrity of the spectrin network is essential for normal cell shape and elasticity. To understand the molecular basis for spectrin's mechanical properties, one must determine how spectrin subunits interact with each other. The newly described crystallographic structures of two consecutive homologous repeats of human alpha-actinin, a member of the spectrin superfamily, shed new light on alpha-actinin interchain binding properties. Here I present evidence that interchain binding at the tail end of the spectrin molecule is likely to occur via a mechanism similar to that observed for alpha-actinin.
Topics: Actinin; Amino Acid Sequence; Animals; Humans; Molecular Sequence Data; Protein Folding; Protein Structure, Secondary; Sequence Homology, Amino Acid; Spectrin
PubMed: 10556504
DOI: 10.1016/s0014-5793(99)01372-1 -
Pesticide Biochemistry and Physiology Nov 2023The female reproductive potential plays a crucial role in reproduction, population dynamics and population maintenance. However, the function of endogenous genes in...
The female reproductive potential plays a crucial role in reproduction, population dynamics and population maintenance. However, the function of endogenous genes in undifferentiated germ cells has been largely unknown in Bactrocera dorsalis. In this study, the conservative analysis showed that α-Spectrin shared a similarity in B. dorsalis and other dipteral flies. Further, the differential expression of α-Spectrin was examined in B. dorsalis by RT-qPCR, and the expression pattern of α-Spectrin protein was identified in female adult ovaries by using immunostaining. During the development of ovary, the change on the number of undifferentiated germ cells was also characterized and analyzed. To understand the function of α-Spectrin in B. dorsalis ovary, the RNAi-based knockdown was conducted, and the RNAi efficiency was examined by RT-qPCR, western blot and bioassay. The results revealed that the α-Spectrin dsRNA could strikingly decrease the expression level of α-Spectrin in ovaries and diminish oviposition and ovary size as a consequence of downregulation of α-Spectrin. Overall, our study facilitates reproductive research on the function of conservative genes in B. dorsalis ovary, which may provide a new insight into seeking novel target genes for pest management control.
Topics: Animals; Female; RNA Interference; Spectrin; Reproduction; Tephritidae
PubMed: 37945250
DOI: 10.1016/j.pestbp.2023.105611 -
Cold Spring Harbor Perspectives in... Dec 2009Nodes of Ranvier and axon initial segments of myelinated nerves, sites of cell-cell contact in early embryos and epithelial cells, and neuromuscular junctions of... (Review)
Review
Nodes of Ranvier and axon initial segments of myelinated nerves, sites of cell-cell contact in early embryos and epithelial cells, and neuromuscular junctions of skeletal muscle all perform physiological functions that depend on clustering of functionally related but structurally diverse ion transporters and cell adhesion molecules within microdomains of the plasma membrane. These specialized cell surface domains appeared at different times in metazoan evolution, involve a variety of cell types, and are populated by distinct membrane-spanning proteins. Nevertheless, recent work has shown that these domains all share on their cytoplasmic surfaces a membrane skeleton comprised of members of the ankyrin and spectrin families. This review will summarize basic features of ankyrins and spectrins, and will discuss emerging evidence that these proteins are key players in a conserved mechanism responsible for assembly and maintenance of physiologically important domains on the surfaces of diverse cells.
Topics: Animals; Ankyrins; Cell Communication; Cell Membrane; Intercellular Junctions; Spectrin
PubMed: 20457566
DOI: 10.1101/cshperspect.a003012 -
The Journal of Physiology Mar 2024Spectrins function together with actin as obligatory subunits of the submembranous cytoskeleton. Spectrins maintain cell shape, resist mechanical forces, and stabilize...
Spectrins function together with actin as obligatory subunits of the submembranous cytoskeleton. Spectrins maintain cell shape, resist mechanical forces, and stabilize ion channel and transporter protein complexes through binding to scaffolding proteins. Recently, pathogenic variants of SPTBN4 (β4 spectrin) were reported to cause both neuropathy and myopathy. Although the role of β4 spectrin in neurons is mostly understood, its function in skeletal muscle, another excitable tissue subject to large forces, is unknown. Here, using a muscle specific β4 spectrin conditional knockout mouse, we show that β4 spectrin does not contribute to muscle function. In addition, we show β4 spectrin is not present in muscle, indicating the previously reported myopathy associated with pathogenic SPTBN4 variants is neurogenic in origin. More broadly, we show that α2, β1 and β2 spectrins are found in skeletal muscle, with α2 and β1 spectrins being enriched at the postsynaptic neuromuscular junction (NMJ). Surprisingly, using muscle specific conditional knockout mice, we show that loss of α2 and β2 spectrins had no effect on muscle health, function or the enrichment of β1 spectrin at the NMJ. Muscle specific deletion of β1 spectrin also had no effect on muscle health, but, with increasing age, resulted in the loss of clustered NMJ Na channels. Together, our results suggest that muscle β1 spectrin functions independently of an associated α spectrin to maintain Na channel clustering at the postsynaptic NMJ. Furthermore, despite repeated exposure to strong forces and in contrast to neurons, muscles do not require spectrin cytoskeletons to maintain cell shape or integrity. KEY POINTS: The myopathy found in pathogenic human SPTBN4 variants (where SPTBN4 is the gene encoding β4 spectrin) is neurogenic in origin. β1 spectrin plays essential roles in maintaining the density of neuromuscular junction Nav1.4 Na channels. By contrast to the canonical view of spectrin organization and function, we show that β1 spectrin can function independently of an associated α spectrin. Despite the large mechanical forces experienced by muscle, we show that spectrins are not required for muscle cell integrity. This is in stark contrast to red blood cells and the axons of neurons.
Topics: Mice; Animals; Humans; Spectrin; Actin Cytoskeleton; Neuromuscular Junction; Muscle, Skeletal; Muscular Diseases
PubMed: 38441922
DOI: 10.1113/JP285894