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Cellular & Molecular Biology Letters 2001This review covers the observations that erythrocyte spectrin has a E2 ubiquitin conjugating enzymatic activity that allows it to transfer ubiquitin to a target site in... (Review)
Review
This review covers the observations that erythrocyte spectrin has a E2 ubiquitin conjugating enzymatic activity that allows it to transfer ubiquitin to a target site in the alpha-spectrin repeats 20/21. The position of this ubiquitination site suggests that ubiquitination may regulate alpha beta spectrin heterodimer nucleation, spectrin-4.1-actin ternary complex formation, and adducin stimulated spectrin-actin attachment in the mature erythrocyte. In sickle cells, which contain altered redox status (high GSSG/GSH ratio), ubiquitin attachment to the E2 and target sites in alpha-spectrin is greatly diminished. We propose that this attenuated ubiquitination of spectrin may be due to glutathiolation of the E2 active site cysteine leading to diminished ubiquitin-spectrin adduct and conjugate formation. Furthermore we propose that lack of ubiquitin-spectrin complex formation leads to dysregulation of the membrane skeleton in mature SS erythrocytes and may diminish spectrin turnover in SS erythropoietic cells via the ubiquitin proteasome machinery. In hippocampal neurons, spectrin is the major ubiquitinated protein and a component of the cytoplasmic ubiquitinated inclusions observed in Alzheimer's and Parkinson's diseases. The two primary neuronal spectrin isoforms: alpha SpI Sigma*/beta SpI Sigma 2 and alpha SpII Sigma 1/beta SpII Sigma 1 are both ubiquitinated. Future work will resolve whether neuronal spectrins also contain E2-ubiquitin conjugating activity and the molecular basis for formation of ubiquitinated inclusions in neurological disorders.
Topics: Amino Acid Sequence; Animals; Binding Sites; Brain; Cysteine Endopeptidases; Erythrocyte Membrane; Erythropoiesis; Hematologic Diseases; Humans; Molecular Sequence Data; Multienzyme Complexes; Nervous System Diseases; Oxidative Stress; Proteasome Endopeptidase Complex; Spectrin; Ubiquitins
PubMed: 11598638
DOI: No ID Found -
Nature Genetics Jul 2021SPTBN1 encodes βII-spectrin, the ubiquitously expressed β-spectrin that forms micrometer-scale networks associated with plasma membranes. Mice deficient in neuronal...
SPTBN1 encodes βII-spectrin, the ubiquitously expressed β-spectrin that forms micrometer-scale networks associated with plasma membranes. Mice deficient in neuronal βII-spectrin have defects in cortical organization, developmental delay and behavioral deficiencies. These phenotypes, while less severe, are observed in haploinsufficient animals, suggesting that individuals carrying heterozygous SPTBN1 variants may also show measurable compromise of neural development and function. Here we identify heterozygous SPTBN1 variants in 29 individuals with developmental, language and motor delays; mild to severe intellectual disability; autistic features; seizures; behavioral and movement abnormalities; hypotonia; and variable dysmorphic facial features. We show that these SPTBN1 variants lead to effects that affect βII-spectrin stability, disrupt binding to key molecular partners, and disturb cytoskeleton organization and dynamics. Our studies define SPTBN1 variants as the genetic basis of a neurodevelopmental syndrome, expand the set of spectrinopathies affecting the brain and underscore the critical role of βII-spectrin in the central nervous system.
Topics: Animals; Genes, Dominant; Genetic Association Studies; Genetic Predisposition to Disease; Genetic Variation; Heterozygote; Humans; Mice; Neurodevelopmental Disorders; Phenotype; Spectrin
PubMed: 34211179
DOI: 10.1038/s41588-021-00886-z -
Sub-cellular Biochemistry 2017Dystrophin and Spectrin are two proteins essential for the organization of the cytoskeleton and for the stabilization of membrane cells. The comparison of these two... (Review)
Review
Dystrophin and Spectrin are two proteins essential for the organization of the cytoskeleton and for the stabilization of membrane cells. The comparison of these two sister proteins, and with the dystrophin homologue utrophin, enables us to emphasise that, despite a similar topology with common subdomains and a common structural basis of a three-helix coiled-coil, they show a large range of dissimilarities in terms of genetics, cell expression and higher level structural organisation. Interactions with cellular partners, including proteins and membrane phospholipids, also show both strikingly similar and very different behaviours. The differences between dystrophin and spectrin are also illustrated by the large variety of pathological anomalies emerging from the dysfunction or the absence of these proteins, showing that they are keystones in their function of providing a scaffold that sustains cell structure.
Topics: Amino Acid Sequence; Animals; Cytoskeleton; Dystrophin; Humans; Protein Conformation; Spectrin
PubMed: 28101868
DOI: 10.1007/978-3-319-49674-0_12 -
Biology of the Cell Mar 2011Although actin is a relevant component of the plant nucleus, only three nuclear ABPs (actin-binding proteins) have been identified in plants to date: cofilin, profilin... (Review)
Review
BACKGROUND INFORMATION
Although actin is a relevant component of the plant nucleus, only three nuclear ABPs (actin-binding proteins) have been identified in plants to date: cofilin, profilin and nuclear myosin I. Although plants lack orthologues of the main structural nuclear ABPs in animals, such as lamins, lamin-associated proteins and nesprins, their genome does contain sequences with spectrin repeats and N-terminal calponin homology domains for actin binding that might be distant relatives of spectrin. We investigated here whether spectrin-like proteins could act as structural nuclear ABPs in plants.
RESULTS
We have investigated the presence of spectrins in Allium cepa meristematic nuclei by Western blotting, confocal and electron microscopy, using antibodies against α- and β-spectrin chains that cross-react in plant nuclei. Their role as nuclear ABPs was analysed by co-immunoprecipitation and IF (immunofluorescence) co-localization and their association with the nuclear matrix was investigated by sequential extraction of nuclei with non-ionic detergent, and in low- and high-salt buffers after nuclease digestion. Our results demonstrate the existence of several spectrin-like proteins in the nucleus of onion cells that have different intranuclear distributions in asynchronous meristematic populations and associate with the nuclear matrix. These nuclear proteins co-immunoprecipitate and co-localize with actin.
CONCLUSIONS
These results reveal that the plant nucleus contains spectrin-like proteins that are structural nuclear components and function as ABPs. Their intranuclear distribution suggests that plant nuclear spectrin-like proteins could be involved in multiple nuclear functions.
Topics: Binding Sites; Cell Nucleus; Flagella; Fluorescent Antibody Technique; Microfilament Proteins; Models, Biological; Plant Proteins; Spectrin; Trypanosomatina
PubMed: 21118155
DOI: 10.1042/BC20100083 -
CRC Critical Reviews in Biochemistry 1988This review begins with a complete discussion of the erythrocyte spectrin membrane skeleton. Particular attention is given to our current knowledge of the structure of... (Review)
Review
This review begins with a complete discussion of the erythrocyte spectrin membrane skeleton. Particular attention is given to our current knowledge of the structure of the RBC spectrin molecule, its synthesis, assembly, and turnover, and its interactions with spectrin-binding proteins (ankyrin, protein 4.1, and actin). We then give a historical account of the discovery of nonerythroid spectrin. Since the chicken intestinal form of spectrin (TW260/240) and the brain form of spectrin (fodrin) are the best characterized of the nonerythroid spectrins, we compare these molecules to RBC spectrin. Studies establishing the existence of two brain spectrin isoforms are discussed, including a description of the location of these spectrin isoforms at the light- and electron-microscope level of resolution; a comparison of their structure and interactions with spectrin-binding proteins (ankyrin, actin, synapsin I, amelin, and calmodulin); a description of their expression during brain development; and hypotheses concerning their potential roles in axonal transport and synaptic transmission.
Topics: Animals; Humans; Spectrin
PubMed: 3048888
DOI: 10.3109/10409238809088319 -
Cellular and Molecular Biology... Oct 2005This review covers the observations leading to the conclusion that erythrocyte spectrin is a chimeric E2/E3 ubiquitin conjugating/ligating enzyme and the impact of this... (Review)
Review
This review covers the observations leading to the conclusion that erythrocyte spectrin is a chimeric E2/E3 ubiquitin conjugating/ligating enzyme and the impact of this activity on the cell. Spectrin is important for the shape and the physical properties of the red blood cell, such as deformability and resistance to mechanical stress. The involvement of RBC spectrin in the ubiquitination process has been demonstrated. Human erythrocyte alpha-spectrin can facilitate formation of ubiquitin-spectrin adducts and conjugates in cell free systems (28). Computer analysis revealed domains that contained significant homologies to known consensus catalytic E2 and E3 sequences, and allowed us to develop a model for alpha-spectrin ubiquitin conjugating enzyme (E2) and ubiquitin protein ligase (E3) enzymatic activities. The model has been tested and the precise E2/E3 site(s) identified by site-specific mutational analyses using a GST-fusion alpha-spectrin(2005-2415) recombinant in an in vitroubiquitination assay (26). The results indicated that cysteine 2071 and cysteine 2100 are critical for alpha-spectrin(2005-2415) E2/E3 activity as expected. However, both Cys2071 and Cys2100 are capable of transferring ubiquitin from an E1 enzyme to target sites within alpha-spectrin(2005-2415). This revealed a redundancy of function for human RBC spectrin's chimeric E2/E3 ubiquitin conjugating/ligating activity. Since spectrin is the major structural component of the erythrocyte membrane skeleton, and it constitutes 20% of the total RBC membrane protein, its ubiquitination enzymatic activity could play an important role in both erythropoietic cells and mature RBCs. This could also be one reason for evolving this redundancy of function.
Topics: Humans; Models, Molecular; Spectrin; Ubiquitin; Ubiquitin-Conjugating Enzymes; Ubiquitin-Protein Ligases
PubMed: 16405856
DOI: No ID Found -
Journal of Cell Science Aug 2022Spectrins are large, evolutionarily well-conserved proteins that form highly organized scaffolds on the inner surface of eukaryotic cells. Their organization in... (Review)
Review
Spectrins are large, evolutionarily well-conserved proteins that form highly organized scaffolds on the inner surface of eukaryotic cells. Their organization in different cell types or cellular compartments helps cells withstand mechanical challenges with unique strategies depending on the cell type. This Review discusses our understanding of the mechanical properties of spectrins, their very distinct organization in red blood cells and neurons as two examples, and the contribution of the scaffolds they form to the mechanical properties of these cells.
Topics: Actin Cytoskeleton; Axons; Erythrocytes; Neurons; Spectrin
PubMed: 35972759
DOI: 10.1242/jcs.259356 -
Cellular and Molecular Life Sciences :... Jan 2012This review focuses on the recent advances in functions of spectrins in non-erythroid cells. We discuss new data concerning the commonly known role of the spectrin-based... (Review)
Review
This review focuses on the recent advances in functions of spectrins in non-erythroid cells. We discuss new data concerning the commonly known role of the spectrin-based skeleton in control of membrane organization, stability and shape, and tethering protein mosaics to the cellular motors and to all major filament systems. Particular effort has been undertaken to highlight recent advances linking spectrin to cell signaling phenomena and its participation in signal transduction pathways in many cell types.
Topics: Animals; Caenorhabditis elegans Proteins; Cell Adhesion; Cell Cycle Proteins; Cytoskeleton; Drosophila Proteins; Humans; Membrane Microdomains; Mice; Protein Isoforms; Protein Processing, Post-Translational; Signal Transduction; Spectrin
PubMed: 21877118
DOI: 10.1007/s00018-011-0804-5 -
ELife Jun 2023Spectrins are membrane cytoskeletal proteins generally thought to function as heterotetramers comprising two α-spectrins and two β-spectrins. They influence cell shape...
Spectrins are membrane cytoskeletal proteins generally thought to function as heterotetramers comprising two α-spectrins and two β-spectrins. They influence cell shape and Hippo signaling, but the mechanism by which they influence Hippo signaling has remained unclear. We have investigated the role and regulation of the β-heavy spectrin (β-spectrin, encoded by the gene) in wing imaginal discs. Our results establish that β-spectrin regulates Hippo signaling through the Jub biomechanical pathway due to its influence on cytoskeletal tension. While we find that α-spectrin also regulates Hippo signaling through Jub, unexpectedly, we find that β-spectrin localizes and functions independently of α-spectrin. Instead, β-spectrin co-localizes with and reciprocally regulates and is regulated by myosin. and experiments support a model in which β-spectrin and myosin directly compete for binding to apical F-actin. This competition can explain the influence of β-spectrin on cytoskeletal tension and myosin accumulation. It also provides new insight into how β-spectrin participates in ratcheting mechanisms associated with cell shape change.
Topics: Animals; Actin Cytoskeleton; Cytoskeleton; Drosophila; Drosophila Proteins; Membrane Proteins; Myosin Type II; Spectrin
PubMed: 37367948
DOI: 10.7554/eLife.84918 -
Current Topics in Membranes 2016Ankyrins are membrane-associated proteins that together with their spectrin partners are responsible for micron-scale organization of vertebrate plasma membranes,... (Review)
Review
Ankyrins are membrane-associated proteins that together with their spectrin partners are responsible for micron-scale organization of vertebrate plasma membranes, including those of erythrocytes, excitable membranes of neurons and heart, lateral membrane domains of columnar epithelial cells, and striated muscle. Ankyrins coordinate functionally related membrane transporters and cell adhesion proteins (15 protein families identified so far) within plasma membrane compartments through independently evolved interactions of intrinsically disordered sequences with a highly conserved peptide-binding groove formed by the ANK repeat solenoid. Ankyrins are coupled to spectrins, which are elongated organelle-sized proteins that form mechanically resilient arrays through cross-linking by specialized actin filaments. In addition to protein interactions, cellular targeting and assembly of spectrin/ankyrin domains also critically depend on palmitoylation of ankyrin-G by aspartate-histidine-histidine-cysteine 5/8 palmitoyltransferases, as well as interaction of beta-2 spectrin with phosphoinositide lipids. These lipid-dependent spectrin/ankyrin domains are not static but are locally dynamic and determine membrane identity through opposing endocytosis of bulk lipids as well as specific proteins. A partnership between spectrin, ankyrin, and cell adhesion molecules first emerged in bilaterians over 500 million years ago. Ankyrin and spectrin may have been recruited to plasma membranes from more ancient roles in organelle transport. The basic bilaterian spectrin-ankyrin toolkit markedly expanded in vertebrates through gene duplications combined with variation in unstructured intramolecular regulatory sequences as well as independent evolution of ankyrin-binding activity by ion transporters involved in action potentials and calcium homeostasis. In addition, giant vertebrate ankyrins with specialized roles in axons acquired new coding sequences by exon shuffling. We speculate that early axon initial segments and epithelial lateral membranes initially were based on spectrin-ankyrin-cell adhesion molecule assemblies and subsequently served as "incubators," where ion transporters independently acquired ankyrin-binding activity through positive selection.
Topics: Adaptation, Physiological; Animals; Ankyrins; Cell Membrane; Humans; Spectrin; Vertebrates
PubMed: 26781832
DOI: 10.1016/bs.ctm.2015.10.001