Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Spectrin”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 811 records · Page 45Linked to original sources
PubMed1991

Resistance to malaria in ankyrin and spectrin deficient mice.

Inbred mice carrying mutations in ankyrin and/or spectrin synthesis and assembly were studied for their ability to support the growth of the rodent malarias, Plasmodium chabaudi adami and P. berghei, in vivo. Mice carrying the nb/nb (normoblastosis) mutation which do not synthesize ankyrin and therefore also have a deficiency in membrane-bound spectrin, were refractory to P. chabaudi adami, which invades mature erythrocytes and to P. berghei, which invades reticulocytes. Similarly, sph/sph mice which do not synthesize the alpha chain of spectrin but do synthesize ankyrin, were also resistant to both parasites. The heterozygote for the nb defect (nb/+) exhibited a diminution of parasitaemia. We conclude that the host cell spectrin may be necessary for the invasion and/or growth of rodent malarial parasites.

Anemia↗
PubMed1980

Properties and structural role of the subunits of human spectrin.

The subunits of spectrin from human erythrocytes were separated by ion-exchange chromatography on hydroxyapatite in the presence of urea. When renatured from the urea solution they are found to be monomeric, although the smaller subunit (band 2) is prone to aggregation. In shape, solubility and secondary structure the subunits resemble the native spectrin dimer, indicating that subunit interaction is not essential for maintaining the native conformation. When the subunits are recombined, a dimer with the sedimentation coefficient of the native species is formed. This constitutes direct evidence that native spectrin is a heterodimer, rather than a mixture containing homologous and heterologous species. The interaction of the separated subunits with the chymotryptic fragment of the spectrin-binding protein (protein 2.1, or ankyrin) of the erythrocyte membrane was studied. Only the smaller subunit has the ability to bind, and thus presumably contains the site by which the cytoskeleton is attached to the plasma membrane. On the other hand, the formation of a complex with F-actin and protein 4.1 requires the presence of both subunits. A complex of these proteins with band 2 is formed, however, when traces of an additional, as yet unidentified, protein are present.

Adult↗
PubMed1992

Actin and neurofilament binding domain of brain spectrin beta subunit.

Tryptic digestion of brain spectrin generates a number of fragments from alpha and beta subunits; when these fragments are incubated with F-actin or neurofilament light subunit, four of them with molecular masses below 30 kDa sediment with the cytoskeleton structures. A selective purification of these fragments by ammonium sulfate fractionation and butyl-Sepharose chromatography has been achieved. Two fragments with molecular masses of 28 and 23 kDa bind to F-actin. Native brain spectrin causes half-maximal inhibition of the association at a concentration of 3 microM. Protein sequencing indicates that the actin-binding domain is contained in the beta subunit, in a stretch of amino acids at the N terminus from Ala43 (28-kDa fragment) or from Met104 (23-kDa fragment) and terminate probably at the C-terminal Lys288 or Lys284. Amino acids are numbered by reference to the sequence of the Drosophila beta subunit. The 28-kDa fragment also binds to the low-molecular-mass subunit of neurofilaments; brain spectrin heterodimer disrupts this binding. Hence, spectrin binds to F-actin and to neurofilaments via a common binding domain.

Actins↗
PubMed1993

Corticosterone exacerbates kainate-induced alterations in hippocampal tau immunoreactivity and spectrin proteolysis in vivo.

Aberrant elevations in intracellular calcium levels, promoted by the excitatory amino acid glutamate, may be a final common mediator of the neuronal damage that occurs in hypoxic-ischemic and seizure disorders. Glutamate and altered neuronal calcium homeostasis have also been proposed to play roles in more chronic neurodegenerative disorders, including Alzheimer's disease. Any extrinsic factors that may augment calcium levels during such disorders may significantly exacerbate the resulting damage. Glucocorticoids (GCs), the adrenal steroid hormones released during stress, may represent one such extrinsic factor. GCs can exacerbate hippocampal damage induced by excitotoxic seizures and hypoxia-ischemia, and we have observed recently that GCs elevate intracellular calcium levels in hippocampal neurons. We now report that the excitotoxin kainic acid (KA) can elicit antigenic changes in the microtubule-associated protein tau similar to those seen in the neurofibrillary tangles of Alzheimer's disease. KA induced a transient increase in the immunoreactivity of hippocampal CA3 neurons towards antibodies that recognize aberrant forms of tau (5E2 and Alz-50). The tau immunoreactivity appeared within 3 h of KA injection, preceded extensive neuronal damage, and subsequently disappeared as neurons degenerated. KA also caused spectrin breakdown, indicating the involvement of calcium-dependent proteases. Physiological concentrations of corticosterone (the species-typical GC of rats) enhanced the neuronal damage induced by KA and, critically, enhanced the intensity of tau immunoreactivity and spectrin breakdown. Moreover, the GC enhancement of spectrin proteolysis was prevented by energy supplementation, supporting the hypothesis that GC disruption of calcium homeostasis in the hippocampus is energetic in nature. Taken together, these findings demonstrate that neurofibrillary tangle-like alterations in tau, and spectrin breakdown, can be induced by excitatory amino acids and exacerbated by GCs in vivo.

Animals↗
PubMed1993

Crystal structure of the repetitive segments of spectrin.

The elongated proteins of the spectrin family (dystrophin, alpha-actinin, and spectrin) contain tandemly repeated segments and form resilient cellular meshworks by cross-linking actin filaments. The structure of one of the repetitive segments of alpha-spectrin was determined at a 1.8 angstrom resolution. A segment consists of a three-helix bundle. A model of the interface between two tandem segments suggests that hydrophobic interactions between segments may constrain intersegment flexibility. The helix side chain interactions explain how mutations that are known to produce hemolytic anemias disrupt spectrin associations that sustain the integrity of the erythrocyte membrane.

Amino Acid Sequence↗
PubMed1990

The oligomeric state of spectrin in the rat erythrocyte membrane skeleton.

The oligomeric state of spectrin in the erythrocyte membrane skeleton of the rat was investigated following extraction in a low ionic strength buffer for 24 and 96 h. All analyses were quantitatively compared with preparations from human erythrocyte membranes. After nondenaturing agarose-polyacrylamide gel electrophoresis, the human samples revealed their characteristic spectrin oligomer pattern; there were high molecular weight complexes near the origin of the gel, followed by several high order oligomers, tetramers, and dimers. The pattern in the rat membrane skeleton also included tetramers and a high molecular weight complex band, but had only one oligomer and no dimers. With time the high molecular weight complex diminished and oligomers accumulated in both the rat and human, while dimers accumulated only in the human and tetramers accumulated only in the rat. Tetramers decreased with time in the human. Extraction of spectrin increased with time and was greater from rat than the human red cell membrane at both time points. The percentage of spectrin and actin in the low ionic strength extract was similar between species, as analyzed by SDS-polyacrylamide electrophoresis, staining, and densitometry. Proteins 4.1 and 4.9 were present in greater percentages in the human. The only temporal effect on monomeric protein composition was an increase of protein A in the rat. There was no species difference in protein A percentage at 24 h, but at 96 h the rat was greater than the human. The results suggest that there are significant differences in the structural arrangement of the rat and human erythrocyte membrane skeleton.

Adult↗
PubMed1986

The neural cell spectrin skeleton: a review.

The discovery of nonerythroid spectrin (Goodman et al., Proc. Natl. Acad. Sci. USA 78: 7570-7574, 1981) has generated interest equivalent to that occurring upon the identification of nonmuscle actin and myosin. Brain spectrin has become the best-studied member of the nonerythroid spectrin family of molecules. In this review, we discuss the structure and functional interactions of brain spectrin, as a prelude to attempting to resolve what are some of the more controversial questions in the field. We finish with a discussion of what may be the most profitable directions for future research.

Animals↗
PubMed2006

Alpha-II-spectrin after controlled cortical impact in the immature rat brain.

Proteolytic processing plays an important role in regulating a wide range of important cellular functions, including processing of cytoskeletal proteins. Loss of cytoskeletal proteins such as spectrin is an important characteristic in a variety of acute central nervous system injuries including ischemia, spinal cord injury and traumatic brain injury (TBI). The literature contains extensive information on the proteolytic degradation of alpha-II-spectrin after TBI in the adult brain. By contrast, there is limited knowledge on the characteristics and relevance of these important processes in the immature brain. The present experiments examine TBI-induced proteolytic processing of alpha-II-spectrin after TBI in the immature rat brain. Distinct proteolytic products resulting from the degradation of the cytoskeletal protein alpha-II-spectrin by calpain and caspase 3 were readily detectable in cortical brain parenchyma and cerebrospinal fluid after TBI in immature rats.

Animals↗
PubMed1994

Protein 4.1 deficiency associated with an altered binding to the spectrin-actin complex of the red cell membrane skeleton.

Protein 4.1 has been defined as a major component of the subcortical skeleton of erythrocytes. It binds the spectrin--actin scaffold through a 10-kD internal domain. This binding requires an essential 21-amino acid sequence motif, Motif I, which is retained by alternative splicing at the late stage of erythroid differentiation. We here analyze the molecular basis of heterozygous 4.1(-) hereditary elliptocytosis, associated with protein 4.1 partial deficiency, in nine related French families. cDNA sequencing revealed a single codon deletion (AAA) resulting in a lysine residue deletion within the 10-kD binding domain, 3' of Motif I. The mutated allele was designated allele 4.1 Aravis. In order to assess the functional effect of the codon deletion, recombinant 10-kD constructs were made and various binding assays were performed using spectrin, purified spectrin-actin complex, or red cell membranes. These experiments demonstrated that the deletion of the Lys residue clearly prevents the binding capacity. Similar results were obtained with a construct containing the Lys residue but lacking Motif I. These data strongly suggest that the binding site to the spectrin-actin complex must contain the Lys 447 (or 448), and therefore resides not only on Motif I but extends 3' of this essential motif.

Actins↗
PubMed1998

sma-1 encodes a betaH-spectrin homolog required for Caenorhabditis elegans morphogenesis.

Morphogenesis transforms the C. elegans embryo from a ball of cells into a vermiform larva. During this transformation, the embryo increases fourfold in length; present data indicates this elongation results from contraction of the epidermal actin cytoskeleton. In sma-1 mutants, the extent of embryonic elongation is decreased and the resulting sma-1 larvae, although viable, are shorter than normal. We find that sma-1 mutants elongate for the same length of time as wild-type embryos, but at a decreased rate. The sma-1 mutants we have isolated vary in phenotypic severity, with the most severe alleles showing the greatest decrease in elongation rate. The sma-1 gene encodes a homolog of betaH-spectrin, a novel beta-spectrin isoform first identified in Drosophila. sma-1 RNA is expressed in epithelial tissues in the C. elegans embryo: in the embryonic epidermis at the start of morphogenesis and subsequently in the developing pharynx, intestine and excretory cell. In Drosophila, betaH-spectrin associates with the apical plasma membrane of epithelial cells; beta-spectrin is found at the lateral membrane. We propose that SMA-1 is a component of an apical membrane skeleton in the C. elegans embryonic epidermis that determines the rate of elongation during morphogenesis.

Amino Acid Sequence↗
PubMed2000

Hereditary spherocytosis in zebrafish riesling illustrates evolution of erythroid beta-spectrin structure, and function in red cell morphogenesis and membrane stability.

Spectrins are key cytoskeleton proteins with roles in membrane integrity, cell morphology, organelle transport and cell polarity of varied cell types during development. Defects in erythroid spectrins in humans result in congenital hemolytic anemias with altered red cell morphology. Although well characterized in mammals and invertebrates, analysis of the structure and function of non-mammalian vertebrate spectrins has been lacking. The zebrafish riesling (ris) suffers from profound anemia, where the developing red cells fail to assume terminally differentiated erythroid morphology. Using comparative genomics, erythroid beta-spectrin (sptb) was identified as the gene mutated in ris. Zebrafish Sptb shares 62.3% overall identity with the human ortholog and phylogenetic comparisons suggest intragenic duplication and divergence during evolution. Unlike the human and murine orthologs, the pleckstrin homology domain of zebrafish Sptb is not removed in red cells by alternative splicing. In addition, apoptosis and abnormal microtubule marginal band aggregation contribute to hemolysis of mutant erythrocytes, which are features not present in mammalian red cells with sptb defects. This study presents the first genetic characterization of a non-mammalian vertebrate sptb and demonstrates novel features of red cell hemolysis in non-mammalian red cells. Further, we propose that the distinct mammalian erythroid morphology may have evolved from specific modifications of Sptb structure and function.

Amino Acid Sequence↗
PubMed2002

CK2 constitutively associates with and phosphorylates chicken erythroid ankyrin and regulates its ability to bind to spectrin.

Previous analyses have shown that the phosphorylation state of chicken erythroid ankyrin regulates its association with the spectrin cytoskeleton in vivo. Treatment of erythroid cells with serine and threonine phosphatase inhibitors stimulates the hyperphosphorylation of ankyrin and its dissociation from spectrin. In this study, we demonstrate that a kinase that directs the phosphorylation of ankyrin in vivo coprecipitates with ankyrin-containing complexes and has properties identical to CK2. Studies using CK2-specific inhibitors have indicated that all of the phosphorylation events associated with erythroid ankyrin in vivo are CK2 dependent. Furthermore, inhibitor studies combined with in vitro binding analyses have indicated that the phosphorylation of erythroid ankyrin by CK2 regulates its ability to associate with spectrin. Additional analyses revealed that CK2 coprecipitates with ankyrin-3-containing complexes isolated from Madin Darby canine kidney epithelial cells and phosphorylates this epithelial ankyrin isoform in vivo. These results are the first demonstration of a kinase constitutively associating with the ankyrin-spectrin cytoskeleton in erythroid and kidney epithelial cells. This association provides a mechanism for rapidly reorganizing the membrane cytoskeleton in these cell types through the phosphorylation of ankyrin.

Animals↗
PubMed1989

Immunological detection of spectrin during differentiation and in mature ciliated cells from quail oviduct.

A protein that was immunologically related to the erythrocyte and brain alpha-240-subunit and to the brain beta-235-subunit of spectrin was characterized by immunoblotting and was detected by immunofluorescence in the apical part of ciliated cells from quail oviduct. After immunogold-labeling electron immunocytochemistry, spectrin was detected mainly in a fibrillar meshwork located between the proximal parts of the basal bodies. It was also observed to be in contact with the basal foot of basal bodies, but was not found to be associated with the apical plasma membrane. Cilia and microvilli were unlabeled. In contrast, spectrin was detected in close contact with the lateral plasma membrane of mature ciliated cells as well as in stem epithelial cells in unstimulated oviduct. During ciliogenesis induced by estrogen, spectrin gradually appeared at the apex of the cells as the apical cytoskeleton differentiated.

Animals↗
PubMedDate not supplied

Some properties of spectrin-like proteins from Pisum sativum.

Proteins cross-reacting with antibodies directed against alpha- and beta-spectrin were recently detected in plant cells. In this report we have studied the ability of these proteins to interact with other components of membrane skeleton such as ankyrin, f-actin and calmodulin. It was found that the polypeptide of high molecular weight reacting with anti-alpha-spectrin antibody binds calmodulin in Ca(2+)-dependent manner. Protein complexes containing polypeptides cross-reacting with anti-spectrin antibodies interact with muscle f-actin (in co-sedimentation assay) and with erythrocyte ankyrin (ELISA-type assay). These data further substantiate a possibility of occurrence of spectrin-based membrane skeleton in higher plant cells.

Actins↗
PubMed2005

Extending a spectrin repeat unit. II: rupture behavior.

A spectrin repeat unit was subject to extension using cyclic expansion nonequilibrium molecular dynamics. Periodic boundary conditions were used to examine the effects of the contiguous alpha-helical linker on the force response. The measured force-extension curve shows a linear increase in the force response when the spectrin repeat unit is extended by approximately 0.4 nm. After that point, the force response peaks and subsequently declines. The peak in the force response marks the point where the spectrin repeat unit undergoes a change in its material properties from a strongly elastic material to a mostly viscous one, on the timescales of the simulations. The force peak is also correlated with rupture of the alpha-helical linker, and is likely the event responsible for the peaks in the sawtooth-pattern force-extension curves measured by atomic force microscopy experiments. Rupture of the linker involves simultaneously breaking approximately four hydrogen bonds that maintain the alpha-helical linker. After this initial rupture, the linker undergoes simple helix-to-coil transitions as the spectrin repeat unit continues to be extended. The implications of linker rupture in the interpretation of unfolding and atomic force microscopy experiments are also discussed.

Animals↗
PubMed2006

Examining the influence of linkers and tertiary structure in the forced unfolding of multiple-repeat spectrin molecules.

The unfolding pathways of multiple-repeat spectrin molecules were examined using steered molecular dynamics (SMD) simulations to forcibly unfold double- and triple-repeat spectrin molecules. Although SMD has previously been used to study other repeating-domain proteins, spectrin offers a unique challenge in that the linker connecting repeat units has a definite secondary structure, that of an alpha-helix. Therefore, the boundary conditions imposed on a double- or triple-repeat spectrin must be carefully considered if any relationship to the real system is to be deduced. This was accomplished by imposing additional forces on the system which ensure that the terminal alpha-helices behave as if there were no free noncontiguous helical ends. The results of the SMD simulations highlight the importance of the rupture of the alpha-helical linker on the subsequent unfolding events. Rupture of the linker propagates unfolding in the adjacent repeat units by destabilizing the tertiary structure, ultimately resulting in complete unfolding of the affected repeat unit. Two dominant classes of unfolding pathways are observed after the initial rupture of a linker which involve either rupture of another linker (possibly adjacent) or rupture of the basic tertiary structure of a repeat unit. The relationship between the force response observed on simulation timescales and those of experiment or physiological conditions is also discussed.

Binding Sites↗
PubMed2005

The spectrin-associated cytoskeleton in mammalian heart.

The membrane-associated cytoskeleton of the cardiac muscle cell is emerging as an important element in the maintenance of normal cell functioning. Recently it was shown that when proteins (betaII-spectrin, muscle Lim-only protein, ankyrin-B, ankyrin-G) of this system are defective or deficient, cardiac malfunction ensues. It is well-established that the spectrin cytoskeleton is associated with the plasma membrane, but it was only lately demonstrated that its components also lie on internal cell membranes. This is particularly apparent in muscle cells of the heart which contain specialised intracellular membrane compartments particular to this cell type such as the sarcoplasmic reticulum and T-tubules. Cardiomyocytes are subjected to constant mechanical stress. Since their mechanics are controlled through coordination of calcium fluxes mediated via cell membrane-based assemblies, it is imperative that these essential elements withstand the displacement forces of contraction. Cardiomyocyte spectrin locates the multifunctional spectrin/actin-binding and membrane-binding component, protein 4.1, and they act together on the plasma membrane as well as on internal membranes. We have found that cardiac protein 4.1 links to the calcium handling apparatus whilst spectrins connect with the sarcomeric contractile elements of the cell. Overall this assembly fulfils roles in stabilising cardiomyocyte cell membranes and in coordinating the macromolecular protein accumulations which regulate and accomplish cardiac molecular crosstalk, whilst at the same time enabling the muscle cells to resist extreme forces of contraction.

Animals↗
PubMed1981

Phosphate metabolite regulation of spectrin interactions.

The deformability of the erythrocyte membrane is believed to depend upon component interactions in the spectrin, actin and band 4.1 complex. Phosphate metabolites, such as 2,3-diphosphoglycerate (2,3 DPG) will dissociate spectrin from actin and band 4.1. This dissociation by 2,3 DPG is highly pH dependent but does not involve divalent cations, 2,3 DPG hydrolysis or spectrin dephosphorylation. In intact erythrocytes the concentrations of 2,3 DPG and the lipid, triphosphatidyl inositol, are sufficient to cause increased labilization in the spectrin, actin and band 4.1 network.

2,3-Diphosphoglycerate↗