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Biochemical Society Transactions Aug 2009Spectrin is a cytoskeletal protein thought to have descended from an alpha-actinin-like ancestor. It emerged during evolution of animals to promote integration of cells... (Review)
Review
Spectrin is a cytoskeletal protein thought to have descended from an alpha-actinin-like ancestor. It emerged during evolution of animals to promote integration of cells into tissues by assembling signalling and cell adhesion complexes, by enhancing the mechanical stability of membranes and by promoting assembly of specialized membrane domains. Spectrin functions as an (alphabeta([H]))(2) tetramer that cross-links transmembrane proteins, membrane lipids and the actin cytoskeleton, either directly or via adaptor proteins such as ankyrin and 4.1. In the present paper, I review recent findings on the origins and adaptations in this system. (i) The genome of the choanoflagellate Monosiga brevicollis encodes alpha-, beta- and beta(Heavy)-spectrin, indicating that spectrins evolved in the immediate unicellular precursors of animals. (ii) Ankyrin and 4.1 are not encoded in that genome, indicating that spectrin gained function during subsequent animal evolution. (iii) Protein 4.1 gained a spectrin-binding activity in the evolution of vertebrates. (iv) Interaction of chicken or mammal beta-spectrin with PtdInsP(2) can be regulated by differential mRNA splicing, which can eliminate the PH (pleckstrin homology) domain in betaI- or betaII-spectrins; in the case of mammalian betaII-spectrin, the alternative C-terminal region encodes a phosphorylation site that regulates interaction with alpha-spectrin. (v) In mammalian evolution, the single pre-existing alpha-spectrin gene was duplicated, and one of the resulting pair (alphaI) neo-functionalized for rapid make-and-break of tetramers. I hypothesize that the elasticity of mammalian non-nucleated erythrocytes depends on the dynamic rearrangement of spectrin dimers/tetramers under the shearing forces experienced in circulation.
Topics: Animals; Ankyrins; Cytoskeletal Proteins; Evolution, Molecular; Membrane Proteins; Models, Biological; Phylogeny; Spectrin
PubMed: 19614597
DOI: 10.1042/BST0370796 -
The Journal of Neuroscience : the... Jul 2023Neural circuit assembly is a multistep process where synaptic partners are often born at distinct developmental stages, and yet they must find each other and form...
Neural circuit assembly is a multistep process where synaptic partners are often born at distinct developmental stages, and yet they must find each other and form precise synaptic connections with one another. This developmental process often relies on late-born neurons extending their processes to the appropriate layer to find and make synaptic connections to their early-born targets. The molecular mechanism responsible for the integration of late-born neurons into an emerging neural circuit remains unclear. Here, we uncovered a new role for the cytoskeletal protein βII-spectrin in properly positioning presynaptic and postsynaptic neurons to the developing synaptic layer. Loss of βII-spectrin disrupts retinal lamination, leads to synaptic connectivity defects, and results in impaired visual function in both male and female mice. Together, these findings highlight a new function of βII-spectrin in assembling neural circuits in the mouse outer retina. Neurons that assemble into a functional circuit are often integrated at different developmental time points. However, the molecular mechanism that guides the precise positioning of neuronal processes to the correct layer for synapse formation is relatively unknown. Here, we show a new role for the cytoskeletal scaffolding protein, βII-spectrin in the developing retina. βII-spectrin is required to position presynaptic and postsynaptic neurons to the nascent synaptic layer in the mouse outer retina. Loss of βII-spectrin disrupts positioning of neuronal processes, alters synaptic connectivity, and impairs visual function.
Topics: Male; Mice; Female; Animals; Spectrin; Cytoskeletal Proteins; Neurons; Cytoskeleton
PubMed: 37369589
DOI: 10.1523/JNEUROSCI.0063-23.2023 -
FEBS Letters Feb 2002Spectrin repeats are three-helix bundle structures which occur in a large number of diverse proteins, either as single copies or in tandem arrangements of multiple... (Review)
Review
Spectrin repeats are three-helix bundle structures which occur in a large number of diverse proteins, either as single copies or in tandem arrangements of multiple repeats. They can serve structural purposes, by coordination of cytoskeletal interactions with high spatial precision, as well as a 'switchboard' for interactions with multiple proteins with a more regulatory role. We describe the structure of the alpha-actinin spectrin repeats as a prototypical example, their assembly in a defined antiparallel dimer, and the interactions of spectrin repeats with multiple other proteins. The alpha-actinin rod domain shares several features common to other spectrin repeats. (1) The rod domain forms a rigid connection between two actin-binding domains positioned at the two ends of the alpha-actinin dimer. The exact distance and rigidity are important, for example, for organizing the muscle Z-line and maintaining its architecture during muscle contraction. (2) The spectrin repeats of alpha-actinin have evolved to make tight antiparallel homodimer contacts. (3) The spectrin repeats are important interaction sites for multiple structural and signalling proteins. The interactions of spectrin repeats are, however, diverse and defy any simple classification of their preferred interaction sites, which is possible for other domains (e.g. src-homology domains 3 or 2). Nevertheless, the binding properties of the repeats perform important roles in the biology of the proteins where they are found, and lead to the assembly of complex, multiprotein structures involved both in cytoskeletal architecture as well as in forming large signal transduction complexes.
Topics: Actinin; Amino Acid Sequence; Animals; Cytoskeletal Proteins; Protein Structure, Secondary; Protein Subunits; Repetitive Sequences, Amino Acid; Spectrin
PubMed: 11911890
DOI: 10.1016/s0014-5793(01)03304-x -
ELife May 2020Previously, we showed that a hierarchy of spectrin cytoskeletal proteins maintains nodal Na channels (Liu et al., 2020). Here, using mice lacking β1, β4, or β1/β4... (Comparative Study)
Comparative Study
Previously, we showed that a hierarchy of spectrin cytoskeletal proteins maintains nodal Na channels (Liu et al., 2020). Here, using mice lacking β1, β4, or β1/β4 spectrins, we show this hierarchy does not function at axon initial segments (AIS). Although β1 spectrin, together with AnkyrinR (AnkR), compensates for loss of nodal β4 spectrin, it cannot compensate at AIS. We show AnkR lacks the domain necessary for AIS localization. Whereas loss of β4 spectrin causes motor impairment and disrupts AIS, loss of β1 spectrin has no discernable effect on central nervous system structure or function. However, mice lacking both neuronal β1 and β4 spectrin show exacerbated nervous system dysfunction compared to mice lacking β1 or β4 spectrin alone, including profound disruption of AIS Na channel clustering, progressive loss of nodal Na channels, and seizures. These results further define the important role of AIS and nodal spectrins for nervous system function.
Topics: Animals; Ankyrins; Axon Initial Segment; Behavior, Animal; Carrier Proteins; Cells, Cultured; Female; Hippocampus; Male; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Microfilament Proteins; Motor Activity; Protein Domains; Rotarod Performance Test; Seizures; Spectrin; Voltage-Gated Sodium Channels
PubMed: 32425157
DOI: 10.7554/eLife.56629 -
Cell Motility and the Cytoskeleton 1989The purpose of this review on spectrin is to examine the functional properties of this ubiquitous family of membrane skeletal proteins. Major topics include... (Review)
Review
The purpose of this review on spectrin is to examine the functional properties of this ubiquitous family of membrane skeletal proteins. Major topics include spectrin-membrane linkages, spectrin-filament linkages, the subcellular localization of spectrins in various cell types and a discussion of major functional differences between erythroid and nonerythroid spectrins. This includes a summary of studies from our own laboratories on the functional and structural comparison of avian spectrin isoforms which are comprised of a common alpha subunit and a tissue-specific beta subunit. Consequently, the observed differences among these spectrins can be assigned to differences in the properties of the beta subunits.
Topics: Humans; Protein Conformation; Spectrin
PubMed: 2655937
DOI: 10.1002/cm.970120405 -
Protoplasma Aug 2010The cells in animals face unique demands beyond those encountered by their unicellular eukaryotic ancestors. For example, the forces engendered by the movement of... (Review)
Review
The cells in animals face unique demands beyond those encountered by their unicellular eukaryotic ancestors. For example, the forces engendered by the movement of animals places stresses on membranes of a different nature than those confronting free-living cells. The integration of cells into tissues, as well as the integration of tissue function into whole animal physiology, requires specialisation of membrane domains and the formation of signalling complexes. With the evolution of mammals, the specialisation of cell types has been taken to an extreme with the advent of the non-nucleated mammalian red blood cell. These and other adaptations to animal life seem to require four proteins--spectrin, ankyrin, 4.1 and adducin--which emerged during eumetazoan evolution. Spectrin, an actin cross-linking protein, was probably the earliest of these, with ankyrin, adducin and 4.1 only appearing as tissues evolved. The interaction of spectrin with ankyrin is probably a prerequisite for the formation of tissues; only with the advent of vertebrates did 4.1 acquires the ability to bind spectrin and actin. The latter activity seems to allow the spectrin complex to regulate the cell surface accumulation of a wide variety of proteins. Functionally, the spectrin-ankyrin-4.1-adducin complex is implicated in the formation of apical and basolateral domains, in aspects of membrane trafficking, in assembly of certain signalling and cell adhesion complexes and in providing stability to otherwise mechanically fragile cell membranes. Defects in this complex are manifest in a variety of hereditary diseases, including deafness, cardiac arrhythmia, spinocerebellar ataxia, as well as hereditary haemolytic anaemias. Some of these proteins also function as tumor suppressors. The spectrin-ankyrin-4.1-adducin complex represents a remarkable system that underpins animal life; it has been adapted to many different functions at different times during animal evolution.
Topics: Animals; Ankyrins; Calmodulin-Binding Proteins; Cytoskeleton; Erythrocyte Membrane; Eukaryotic Cells; Spectrin
PubMed: 20668894
DOI: 10.1007/s00709-010-0181-1 -
BioEssays : News and Reviews in... Feb 2001It has long been speculated that spectrin, the actin crosslinking and molecular scaffold protein, is involved in the development of apicobasal polarity in epithelia.... (Review)
Review
It has long been speculated that spectrin, the actin crosslinking and molecular scaffold protein, is involved in the development of apicobasal polarity in epithelia. While spectrins can undoubtedly influence the protein content of specific membrane domains, recent genetic evidence indicates that this activity is not necessary for the establishment or maintenance of this axis. Instead, these studies point to critical roles in tissue stability and morphogenesis. A possible role in cellular contractility is highlighted in this review.
Topics: Animals; Erythrocyte Membrane; Forecasting; Humans; Models, Biological; Morphogenesis; Myosins; Spectrin
PubMed: 11169588
DOI: 10.1002/1521-1878(200102)23:2<152::AID-BIES1022>3.0.CO;2-1 -
IUBMB Life May 2022Hemoglobin oxidation due to oxidative stress and disease conditions leads to the generation of ROS (reactive oxygen species) and membrane attachment of hemoglobin...
Hemoglobin oxidation due to oxidative stress and disease conditions leads to the generation of ROS (reactive oxygen species) and membrane attachment of hemoglobin in-vivo, where its redox activity leads to peroxidative damage of membrane lipids and proteins. Spectrin, the major component of the red blood cell (RBC) membrane skeleton, is known to interact with hemoglobin and, here this interaction is shown to increase hemoglobin peroxidase activity in the presence of reducing substrate ABTS (2', 2'-Azino-Bis-3-Ethylbenzothiazoline-6-Sulfonic Acid). It is also shown that in the absence of reducing substrate, spectrin forms covalently cross-linked aggregates with hemoglobin which display no peroxidase activity. This may have implications in the clearance of ROS and limiting peroxidative damage. Spectrin is found to modulate the peroxidase activity of different hemoglobin variants like A, E, and S, and of isolated globin chains from each of these variants. This may be of importance in disease states like sickle cell disease and HbE-β-thalassemia, where increased oxidative damage and free globin subunits are present due to the defects inherent in the hemoglobin variants associated with these diseases. This hypothesis is corroborated by lipid peroxidation experiments. The modulatory role of spectrin is shown to extend to other heme proteins, namely catalase and cytochrome-c. Experiments with free heme and Raman spectroscopy of heme proteins in the presence of spectrin show that structural alterations occur in the heme moiety of the heme proteins on spectrin binding, which may be the structural basis of increased enzyme activity.
Topics: Antioxidants; Catalase; Heme; Hemeproteins; Hemoglobins; Peroxidase; Peroxidases; Reactive Oxygen Species; Spectrin
PubMed: 35184374
DOI: 10.1002/iub.2607 -
The Journal of Physiology Aug 2016Spinocerebellar ataxias (SCAs) are a genetically heterogeneous group of disorders all characterised by postural abnormalities, motor deficits and cerebellar... (Review)
Review
Spinocerebellar ataxias (SCAs) are a genetically heterogeneous group of disorders all characterised by postural abnormalities, motor deficits and cerebellar degeneration. Animal and in vitro models have revealed β-III spectrin, a cytoskeletal protein present throughout the soma and dendritic tree of cerebellar Purkinje cells, to be required for the maintenance of dendritic architecture and for the trafficking and/or stabilisation of several membrane proteins: ankyrin-R, cell adhesion molecules, metabotropic glutamate receptor-1 (mGluR1), voltage-gated sodium channels (Nav ) and glutamate transporters. This scaffold of interactions connects β-III spectrin to a wide variety of proteins implicated in the pathology of many SCAs. Heterozygous mutations in the gene encoding β-III spectrin (SPTBN2) underlie SCA type-5 whereas homozygous mutations cause spectrin associated autosomal recessive ataxia type-1 (SPARCA1), an infantile form of ataxia with cognitive impairment. Loss-of β-III spectrin function appears to underpin cerebellar dysfunction and degeneration in both diseases resulting in thinner dendrites, excessive dendritic protrusion with loss of planarity, reduced resurgent sodium currents and abnormal glutamatergic neurotransmission. The initial physiological consequences are a decrease in spontaneous activity and excessive excitation, likely to be offsetting each other, but eventually hyperexcitability gives rise to dark cell degeneration and reduced cerebellar output. Similar molecular mechanisms have been implicated for SCA1, 2, 3, 7, 13, 14, 19, 22, 27 and 28, highlighting alterations to intrinsic Purkinje cell activity, dendritic architecture and glutamatergic transmission as possible common mechanisms downstream of various loss-of-function primary genetic defects. A key question for future research is whether similar mechanisms underlie progressive cerebellar decline in normal ageing.
Topics: Animals; Cerebellar Ataxia; Cognitive Dysfunction; Humans; Mutation; Spectrin
PubMed: 26821241
DOI: 10.1113/JP271195 -
Communications Biology Jan 2023Fast synaptic inhibition is dependent on targeting specific GABAR subtypes to dendritic and axon initial segment (AIS) synapses. Synaptic GABARs are typically assembled...
Fast synaptic inhibition is dependent on targeting specific GABAR subtypes to dendritic and axon initial segment (AIS) synapses. Synaptic GABARs are typically assembled from α1-3, β and γ subunits. Here, we isolate distinct GABARs from the brain and interrogate their composition using quantitative proteomics. We show that α2-containing receptors co-assemble with α1 subunits, whereas α1 receptors can form GABARs with α1 as the sole α subunit. We demonstrate that α1 and α2 subunit-containing receptors co-purify with distinct spectrin isoforms; cytoskeletal proteins that link transmembrane proteins to the cytoskeleton. β2-spectrin was preferentially associated with α1-containing GABARs at dendritic synapses, while β4-spectrin was associated with α2-containing GABARs at AIS synapses. Ablating β2-spectrin expression reduced dendritic and AIS synapses containing α1 but increased the number of synapses containing α2, which altered phasic inhibition. Thus, we demonstrate a role for spectrins in the synapse-specific targeting of GABARs, determining the efficacy of fast neuronal inhibition.
Topics: Receptors, GABA-A; Spectrin; Synapses; Membrane Proteins; gamma-Aminobutyric Acid
PubMed: 36604600
DOI: 10.1038/s42003-022-04381-x