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PubMed1983

[Congenital hemolytic anemia with erythrocyte thermal instability and defect of spectrin tetrameric polymerization. Study of erythrocyte deformability in a new case of hereditary pyropoikilocytosis using diffraction viscosimetry].

Hereditary pyropoikilocytosis (HPP) is a rare congenital hemolytic anaemia observed so far in patients of black extraction. In many cases, the severity of the anaemia has led to early splenectomy, which uniformly improved the hematological conditions. The disease is characterized by extreme anisocytosis and poikilocytosis with erythrocyte fragmentation. The pathognomonic feature is the abnormal thermal sensitivity of red cells which fragment in vitro at 45-46 degrees C (instead of 49 degrees C in normal subjects). In the case reported here, erythrocyte fragmentation (which appears at 43 degrees C) and increased osmotic fragility are studied using the Ektacytometer. Observation of different erythrocyte fractions isolated by differential centrifugation shows the extreme heterogeneity of the erythrocyte population. Studies of erythrocyte membrane proteins confirm that the disease is related to defective dimer-dimer association of spectrin which is the major membrane skeletal protein. This molecular spectrin abnormality in accounting for the membrane instability is recognized to a lesser degree in the asymptomatic mother. This may be of use in the diagnosis of HPP which is difficult to establish in a transfusion-dependent infant.

Anemia, Hemolytic, Congenital↗
PubMed1982

F-actin-binding and cross-linking properties of porcine brain fodrin, a spectrin-related molecule.

The axonally transported high molecular weight protein fodrin, known to be present in the cortical cytoplasm of neurones and other cells, has been purified to homogeneity and several of its biochemical properties have been characterized. Fodrin is an F-actin-binding and cross-linking protein inducing actin gels. It is composed of two nonidentical polypeptide chains (Mr = 240,000 and 235,000) which form a tetrameric complex of a molecular weight close to 930,000. The similarity of fodrin with tetrameric erythrocyte spectrin is directly shown by rotary shadowed molecules both alone and in interaction with F-actin. The gelation and cross-linking activity of fodrin is influenced both by ionic strength and pH in a manner similar to other cross-linking factors. These results strengthen previous concepts concerning the existence of spectrin-related molecules in nonerythroid cells and point to a possible related function in the submembranous microfilament organization in nonmuscle cells.

Actins↗
PubMed1994

A transmembrane protein-tyrosine phosphatase contains spectrin-like repeats in its extracellular domain.

We report the first chicken transmembrane protein-tyrosine phosphatase, ChPTP lambda, isolated from a brain cDNA library and preB cells. ChPTP lambda has transcripts of about 5.6 kilobases and is abundant in spleen, intestine, and fibroblasts transformed by oncogenic ras or erbA/B. It has five alternative splicing products varying near their amino termini, and the largest one contains 1237 amino acids. The extracellular domain of ChPTP lambda has several features including a Ser/Thr/Pro-rich region, one fibronectin type III module, and spectrin-like repeats (the first case that spectrin-like repeats were found in the non-cytoplasmic compartment). These repeats were also found in other phosphatases, including CD45 and yeast acid phosphatases PHO5 and PHO3. Antibodies to ChPTP lambda recognized several protein species whose M(r) range from 170,000 to 210,000. ChPTP lambda exhibited phosphotyrosine-specific phosphatase activity. Since CD45 also has these features in the extracellular domain and the two protein-tyrosine phosphatases share 70% similarity in the intracellular domains, we propose that ChPTP lambda and CD45 belong to the same gene family.

Alternative Splicing↗
PubMed1993

Location of the human red cell spectrin tetramer binding site and detection of a related "closed" hairpin loop dimer using proteolytic footprinting.

Head-to-head association of two spectrin alpha beta heterodimers to form tetramers involves the formation of two equivalent alpha-beta complexes. The sites on the alpha subunit N-terminal region and beta subunit C-terminal region that form these alpha beta complexes have been identified using protease footprinting and direct binding assays. The existence of a similar previously hypothesized internal head-to-head alpha beta interaction in dimers was also demonstrated. The discrete regions of both subunits that are protected from proteolysis in tetramers and dimers are not due to the laterally associated subunit since head-to-head complexes of a univalent alpha peptide with a univalent beta peptide show similar protection of the same sites. These sites are unshielded immediately after monomers assemble side-to-side to form heterodimers, demonstrating that reconstituted dimers are initially in an "open" conformation. Conversion of open dimers to a closed form through formation of the internal head-to-head alpha beta association, as demonstrated by restoration of protease protection, occurred on a time scale of hours at 0 degrees C. Analysis of peptide binding affinities as well as isolation and sequence analysis of head-to-head alpha beta noncovalent complexes further defined the regions required for association on both subunits. These regions are homologous to the 106-residue repetitive motif that comprises most of both chains. An algorithm designed to improve prediction accuracy of multiple homologous motifs was used to model the conformation of spectrin repetitive motifs as well as the contact regions. In this model, the separate alpha and beta binding sites are incomplete complementary parts of a triple stranded folding unit. Formation of the alpha beta head-to-head complex produces a triple stranded conformational unit that is slightly different from other homologous motifs in the protein. Most hemolytic anemia mutations that are known to disrupt tetramer association are located in the mapped regions, including several mutations that induce a conformational change in the paired subunit.

Amino Acid Sequence↗
PubMed1993

Erythroid and nonerythroid spectrins.

Recent developments have contributed important information to understanding the role of spectrins in the RBC membrane skeleton and nonerythroid cells. Many questions can now be framed, informed by structural knowledge of various spectrin subunit types and alternatively spliced variants, that previously could not have been addressed. Their solution in the coming years will likely lead to further advances with direct relevance to biology and medicine.

Animals↗
PubMed1996

Spatial relationships of utrophin, dystrophin, beta-dystroglycan and beta-spectrin to acetylcholine receptor clusters during postnatal maturation of the rat neuromuscular junction.

At the adult mammalian neuromuscular junction, acetylcholine receptors are concentrated at the tops of the postsynaptic folds and voltage-gated sodium channels are concentrated in their depths. It is likely that this arrangement involves linkage of the ion channels to components of the underlying membrane cytoskeleton. In rats, the mature distribution of acetylcholine receptors arises as part of the developmental remodelling of the junctional region during the first few weeks after birth. We have followed the changes during this period in the distribution of four proteins associated with the postsynaptic cytoskeleton at mature neuromuscular junctions (utrophin, dystrophin, beta-dystroglycan and beta-spectrin) to see if any of them co-localizes with acetylcholine receptors during the remodelling process, as would be required if it serves to link acetylcholine receptors to the cytoskeleton. Each protein was visualized with specific monoclonal antibodies and its distribution at various stages was compared with that of the acetylcholine receptors, labelled with alpha-bungarotoxin. We also related the changes in distribution of these postsynaptic proteins to the main stages in fold formation and, in the Discussion, to reported observations of the accumulation of voltage gated sodium channels during development. Our results show that utrophin labelling is closely co-localized with that of acetylcholine receptors throughout postnatal maturation. beta-dystroglycan labelling is present at most sites of high acetylcholine receptors density throughout maturation although it often extends beyond the region of highest acetylcholine receptors labelling density. By contrast, dystrophin and beta-spectrin labelling is not consistently concentrated at most neuromuscular junctions until after P7 and P14 respectively.

Age Factors↗
PubMed1997

The exon 46-encoded sequence is essential for stability of human erythroid alpha-spectrin and heterodimer formation.

Human erythroid alpha-spectrin alleles responsible for hereditary elliptocytosis (alphaHE alleles) undergo increased incorporation into red blood cell membranes when the polymorphism alphaLELY (LELY: Low Expression LYon) occurs in trans. The alphaLELY polymorphism is characterized by a mutation in exon 40 at codon 1857 (CTA --> GTA, Leu --> Val) and the partial (50%) skipping of exon 46, which encodes residues 2177-2182 (Wilmotte et al, J Clin Invest 91:2091, 1993). Both of these peptide sequence alterations are located within the region of the alpha-chain involved in initiating heterodimer assembly, and either or both mutations could potentially contribute to decreased incorporation of alpha-chains from the alphaLELY allele in heterozygotes into red blood cell membranes. These possibilities were evaluated by testing the protease resistance and in vitro binding properties of normal and mutant recombinant 4-motif alpha subunit peptides containing the dimer initiation region. The two forms of alpha spectrin produced by alternative mRNA splicing of the alphaLELY allele were represented by alpha18-21(1857), a peptide with the codon 1857 mutation and retaining the exon 46 encoded sequence, and alpha18-21(1857-Delta46), a peptide carrying both the 1857 codon mutation and the exon 46 deletion. The properties of these two recombinant peptides were compared with alpha18-21, a peptide with the normal sequence at codon 1857 and retaining the exon 46 encoded sequence. The codon 1857 mutation does not adversely affect dimer formation, but it is responsible for the increased trypsin cleavage between the alphaIV and alphaV domains that was the characteristic feature initially used to identify the alphaLELY (SpalphaV/41) polymorphism (Alloisio et al, J Clin Invest 87:2169, 1991). Deletion of the six amino acids encoded by exon 46 perturbs folding of the alpha21 motif, because this region of the alpha18-21(1857-Delta46) peptide is rapidly degraded and this recombinant peptide is unusually prone to self-aggregation. Exon 46 deletion reduces, but does not eliminate, dimerization. Comparison of mild trypsin proteolytic products from an alphaLELY homozygote and the two alphaLELY recombinant peptides strongly suggests that little, if any, of the 50% of the alpha chains from the alphaLELY allele that contain the exon 46 deletion are incorporated into the mature erythroid membrane. Based on the in vitro analysis of recombinant alphaLELY peptides, the inability of detectable amounts of exon 46(-) alpha chains to assemble into the mature membrane skeleton in vivo is probably due to a combination of decreased dimer binding affinity and increased proteolytic degradation of these mutant chains.

Alleles↗
PubMed1998

Hematopoietic cells from -spectrin-deficient mice are sufficient to induce thrombotic events in hematopoietically ablated recipients.

Thrombotic events are life-threatening complications of human hemolytic anemias such as paroxysmal nocturnal hemoglobinuria, sickle cell disease, and thalassemia. It is not clear whether these events are solely influenced by aberrant hematopoietic cells or also involve aberrant nonhematopoietic cells. Spherocytosis mutant (Spna1(sph)/Spna1(sph); for simplicity referred to as sph/sph) mice develop a severe hemolytic anemia postnatally due to deficiencies in -spectrin in erythroid and other as yet incompletely defined nonerythroid tissues. Thrombotic lesions occur in all adult sph/sph mice, thus providing a hematopoietically stressed model in which to assess putative causes of thrombus formation. To determine whether hematopoietic cells from sph/sph mice are sufficient to initiate thrombi, bone marrow from sph/sph or +/+ mice was transplanted into mice with no hemolytic anemia. One set of recipients was lethally irradiated; the other set was genetically stem cell deficient. All mice implanted with sph/sph marrow, but not +/+ marrow, developed severe anemia and histopathology typical of sph/sph mice. Histological analyses of marrow recipients showed that thrombi were present in the recipients of sph/sph marrow, but not +/+ marrow. The results indicate that the -spectrin-deficient hematopoietic cells of sph/sph mice are the primary causative agents of the thrombotic events.

Anemia, Hemolytic↗
PubMed1975

Calcium and magnesium ATPases of the spectrin fraction of human erythrocytes.

Using a rapid method of preparation, spectrin has been isolated from human erythrocytes and its ATPase activity investigated. The ATPase activity with calcium has two distinct components, one with optimal activity when calcium and ATP are of equal concentration (low-Ca-ATPase) and another which is activated above 1 mM CaCl2 and is maximal at 100 mM CaCl2. There is also a Mg-ATPase with maximal activity at 10 mM MgCl2. The high-Ca-ATPase of spectrin, but not the low-Ca-ATPase, is inhibited by magnesium, while the Mg-ATPase is inhibited by Ca in excess of ATP. None of these activities exhibits the calcium-stimulated magnesium-dependent activity characteristic of the red cell calcium pump.

Adenosine Triphosphatases↗
PubMed1988

Phosphorylation of Plasmodium berghei derived phosphoproteins associated with the host erythrocyte membrane by the spectrin kinase.

Plasmodium berghei derived phosphoproteins are associated with the host erythrocyte membrane. Effectors of the phosphorylation reaction regulate the phosphorylation of the P. berghei derived proteins and spectrin in a similar manner. The spectrin kinase also phosphorylates the P. berghei phosphoproteins in a reconstituted reaction at the same site(s) as the endogenously phosphorylated proteins. These results indicate that a host protein kinase may regulate parasite phosphoproteins during malaria.

Animals↗
PubMed1976

Isoelectric focusing of spectrin components in hereditary spherocytosis.

1. By isoelectric focusing in 8 M urea, spectrin purified from normal human erythrocytes was resolved into 12 to 15 peptide bands differing by their isoelectric point. Most of them were focused between pH 6.4 and 5.2, one at pH 8.7 and some minor components between pH 7.4 and 6.8. 2. The results were not influenced by the erythrocyte population age. 3. Spectrin purified from erythrocytes of five patients with hereditary spherocytosis gave similar isoelectric focusing patterns, with the exception of the lack of the pH 8.7-focused component in two related patients.

Erythrocyte Aging↗
PubMed1982

Actin polymerization induced by calspectin, a calmodulin-binding spectrin-like protein.

We have purified from a membrane fraction of bovine brain a calmodulin-binding protein (calspectin) that shares a number of properties with erythrocyte spectrin: It has a heterodimeric structure with Mr 240 000 and 235 000 and binds to (dimeric form) or crosslinks (tetrameric form) F-actin. We show that calspectin (tetramer) is capable of inducing the polymerization of G-actin to actin filaments by increasing nucleation under conditions where actin alone polymerizes at a much slower rate. Thus, brain calspectin behaves in the same manner as erythrocyte spectrin, supporting the idea that, in conjunction with actin oligomers it comprises the cytoskeletal meshwork underlying the cytoplasmic surface of the nerve cell.

Actins↗
PubMed2006

Identification and characterization of GSRP-56, a novel Golgi-localized spectrin repeat-containing protein.

Spectrin repeat (SR)-containing proteins are important for regulation of integrity of biomembranes, not only the plasma membrane but also those of intracellular organelles, such as the Golgi, nucleus, endo/lysosomes, and synaptic vesicles. We identified a novel SR-containing protein, named GSRP-56 (Golgi-localized SR-containing protein-56), by a yeast two-hybrid method, using a member of the transient receptor potential channel family, TRPV2, as bait. GSRP-56 is an isoform derived from a giant SR-containing protein, Syne-1 (synaptic nuclear envelope protein-1, also referred to as Nesprin-1 or Enaptin), predicted to be produced by alternative splicing. Immunological analysis demonstrated that this isoform is a 56-kDa protein, which is localized predominantly in the Golgi apparatus in cardiomyocytes and C2C12 myoblasts/myotubes, and we found that two SR domains were required both for Golgi targeting and for interaction with TRPV2. Interestingly, overexpression of GSRP-56 resulted in a morphological change in the Golgi structure, characterized by its enlargement of cis-Golgi marker antibody-staining area, which would result partly from fragmentation of Golgi membranes. Our findings indicate that GSRP-56 is a novel, particularly small Golgi-localized member of the spectrin family, which possibly play a role in maintenance of the Golgi structure.

Animals↗
PubMed1984

Distribution of p230, an alpha-spectrin-related polypeptide in normal and psoriatic epidermis and in cultured human keratinocytes.

We studied the localization of p230, an immunoanalogue of erythroid alpha-spectrin, in normal and psoriatic human epidermis and in cultured human keratinocytes. In immunofluorescence microscopy of frozen sections of normal skin a bright cytoplasmic staining was seen in the cortical area of the keratinocytes. Similar staining was also seen in lesional and uninvolved areas of psoriatic epidermis. The pericytoplasmic localization of p230 could also be seen in cultured human keratinocytes: a lamina-like reticular staining was seen mostly confined to the ventral cytoplasmic aspect and to junctional areas of the cells. Immunoblotting of electrophoretically separated polypeptides of epidermal cells revealed a distinct polypeptide of Mr 230 kD. The results indicate that alpha-spectrin-like polypeptides form a major cytoskeletal framework in human epidermal cells in both normal and psoriatic skin.

Cells, Cultured↗
PubMed2005

Relationships between DNA methylation and expression in erythrocyte membrane protein (band 3, protein 4.2, and beta-spectrin) genes during human erythroid development and differentiation.

Red cell membrane proteins are sequentially expressed during erythroid development and differentiation. Spectrins have already been synthesized in early erythroid precursors such as pronormoblasts, and band 3 (B3) appears at nearly the same stage. Protein 4.1 appears next, followed by protein 4.2 (P4.2) at the very late erythroblast stage. The methylation states of the promoter 5'-CG-3' sites are known to be linked to the regulation of promoter function by modulating DNA-protein interactions and the structure of chromatin. Hence, the genes for B3, P4.2, and beta-spectrin (beta-SP) appear to be suitable models to study the relationship between methylation of promoter 5'-CG-3' sites and the sequential expression of genes during human erythroid development and differentiation. We have examined methylation profiles in the promoter regions of the genes (ELB42, EPB3, and SPTB) for the human erythroid membrane proteins P4.2, B3, and beta-SP by applying the bisulfite genomic sequencing method. Our results demon strate the following: (1) The promoter regions of EPB3 and ELB42 are extensively methylated in DNA from human peripheral blood mononuclear cells, but the SPTB promoter is totally unmethylated. (2) During erythroid differentiation, DNA methylation patterns change as follows: (a) ELB42 is unmethylated in DNA from erythroid-committed blastic cells, such as the human cell lin UT-7/EPO, but is methylated in erythroblasts from peripheral blood burst-forming unit erythroid (BFU-E) in the second phase of the liquid-culture method. Messenger RNA (mRNA) from ELB42 is first detected in early erythroblasts, and P4.2 is expressed in late erythroblasts. (b) In contrast, EPB3 is consistently methylated in UT-7/EPO cells and in cultured erythroblasts from BFU-E from human peripheral blood. B3 mRNA and protein are already expressed in early erythroblasts. (c) SPTB remains unmethylated in human DNA from UT-7/EPO cells and from cultured erythroblasts. These results document the diversity of the reactions of human promoter sequences to the modulating influence of DNA methylation. Whereas the human SPTB promoter conforms to expectations in that it is unmethylated and fully active throughout erythroid development, high levels of promoter methylation correlate with promoter activity for the EPB3 and ELB42 genes during their sequential activation in erythrocyte differentiation.

Cell Differentiation↗
PubMed1997

Helix bundles and coiled coils in alpha-spectrin and tropomyosin: a theoretical CD study.

The dipole interaction model is used to investigate the effects of interactions between helices and supertwisting of helices by determining whether the predicted UV absorption and CD spectra for the three-helix bundle and coiled coil are significantly different from spectra for the single straight alpha-helix. Crystallographic data by Yan et al. for alpha-spectrin are used to construct a three-helix bundle of poly(L-alanine) modeling the protein. Backbone torsion angles represented by Fourier series are used to generate supertwisted helices and coiled coil models of poly(L-alanine) that have pitch, radius, and residue repeat similar to experimental crystallographic data on tropomyosin. Calculated CD spectra are compared with available experimental data. Theoretical spectra for the three-helix bundle and the supertwisted structures are quite similar to predictions for the straight alpha-helix of the same length with similar torsion angles, suggesting that CD is primarily dependent on the average backbone conformation and would not be a sensitive tool for distinguishing between single straight helices and closely packed or twisted alpha-helices.

Circular Dichroism↗