Abnormal oxidant sensitivity and beta-chain structure of spectrin in hereditary spherocytosis associated with defective spectrin-protein 4.1 binding.

Becker, Pamela S.; Morrow, Jon S.; Lux, Samuel E.

doi:10.1172/jci113104

Cited by 46 publications

(17 citation statements)

References 65 publications

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“…There was also spectrin deficiency to 80% of the normal quantity (10), a level which is comparable with that of the autosomal dominant type of HS. The one unusual feature noted in this kindred was prominent acanthocytosis, even before splenectomy, among the affected individuals (9,10).…”

Section: Introductionsupporting

confidence: 60%

“…One cannot predict whether the mutant protein would be unstable in vivo on the basis of its instability in the bacterial expression system. However, it was found previously that the HS spectrin was more sensitive to oxidation ( 10). It is also interesting that there was a lower proportion of mutant spectrin isolated by protein 4.1 affinity chromatography (9) than would be predicted in a heterozygous individual (40 vs. 50%), implying that there is indeed instability of the protein in vivo.…”

Section: Resultsmentioning

confidence: 85%

“…In one of the kindreds, previous studies demonstrated that approximately 40% of the spectrin was unable to bind protein 4.1 (9) and that there was abnormal chymotryptic digestion of the isolated f spectrin in individuals from this kindred (10). There was also spectrin deficiency to 80% of the normal quantity (10), a level which is comparable with that of the autosomal dominant type of HS. The one unusual feature noted in this kindred was prominent acanthocytosis, even before splenectomy, among the affected individuals (9,10).…”

Section: Introductionmentioning

confidence: 74%

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Beta spectrin kissimmee: a spectrin variant associated with autosomal dominant hereditary spherocytosis and defective binding to protein 4.1.

et al. 1993

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We analyzed the DNA sequence of the cDNA encoding the NH2 terminal region of ft spectrin from members of a kindred with autosomal dominant hereditary spherocytosis associated with defective protein 4.1 binding. We found a point mutation at codon 202 within the 272 amino acid NH2-terminal region of 13 spectrin. TGG was changed to CGG, resulting in the replacement of tryptophan by arginine. The base change eliminates a normally occurring PvuII restriction site and creates a new MspI site. This finding enabled rapid detection or exclusion of the mutation at the DNA level among the family members, including one member for whom this analysis was performed prenatally. The mutation was found only in the affected family members and occurred as a de novo mutation in the proband. It has not been found in 20 other kindreds. The recombinant peptide derived from the normal cDNA retains the capacity to sediment with protein 4.1 and F-actin. The mutant peptide spontaneously degrades. This variant represents both the first point mutation and the first,8 spectrin mutation demonstrated in autosomal dominant hereditary spherocytosis. Furthermore, the mutation is located within a conserved sequence among spectrinlike proteins and may define an amino acid critical for protein 4.1 binding activity. (J. Clin. Invest. 1993. 92:612-616.)

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Section: Introductionsupporting

confidence: 60%

Section: Resultsmentioning

confidence: 85%

Section: Introductionmentioning

confidence: 74%

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Beta spectrin kissimmee: a spectrin variant associated with autosomal dominant hereditary spherocytosis and defective binding to protein 4.1.

et al. 1993

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“…There was no binding to GST or to other spectrin fragments. The ␣17-C construct comprises repeats 17,18,19,20,21, and the C-terminal element with four EF-hands. We next examined the binding of FIa1 to all these parts of the large fragment individually and obtained a positive result for only one of them.…”

Section: Mapping the Pfemp3 Binding Site In Spectrin-mentioning

confidence: 99%

Plasmodium falciparum Erythrocyte Membrane Protein 3 (PfEMP3) Destabilizes Erythrocyte Membrane Skeleton

Pei

Guo

Coppel

et al. 2007

Journal of Biological Chemistry

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Plasmodium falciparum erythrocyte membrane protein 3 (PfEMP3) is a parasite-derived protein that appears on the cytoplasmic surface of the host cell membrane in the later stages of the parasite's development where it associates with membrane skeleton. We have recently demonstrated that a 60-residue fragment (FIa1, residues 38 -97) of PfEMP3 bound to spectrin. Here we show that this polypeptide binds specifically to a site near the C terminus of ␣-spectrin at the point that spectrin attaches to actin and protein 4.1R in forming the junctions of the membrane skeletal network. We further show that this polypeptide disrupts formation of the ternary spectrin-actin-4.1R complex in solution. Importantly, when incorporated into the cell, the PfEMP3 fragment causes extensive reduction in shear resistance of the cell. We conjecture that the loss of mechanical cohesion of the membrane may facilitate the exit of the mature merozoites from the cell.The intraerythrocytic form of Plasmodium falciparum, the agent of the most severe type of human malaria, exports many (according to a proteomic estimate, up to 400) proteins into the host cell in the course of its growth and development (1-3). Certain of these proteins are known to associate with the host cell membrane skeleton and thereby modify its structure and properties. Among the changes that have been reported are an altered morphology, an increased membrane rigidity, and an enhanced propensity to adhere to the vascular endothelium (4). Several such proteins that bind to the red cell membrane skeleton have so far been characterized. When the parasite first invades red cells, it deposits RESA (the ring parasite-infected erythrocyte surface antigen) at the membrane skeleton of the newly invaded cell where it binds to spectrin and protects against thermal damage (5-7). As the intracellular parasite further matures, it traffics further proteins to the skeleton. P. falciparum erythrocyte membrane protein 1, or PfEMP1, 2 is inserted into the red cell membrane and its extracellular domain adheres to receptors on endothelial cells (8). PfEMP1 clusters on the red cell surface at dimpled areas called knobs by binding of its intracellular domain to the parasite-encoded protein KAHRP (knob-associated histidine-rich protein) from which knobs are formed (9) and to spectrin and actin (10). KAHRP itself is stabilized at the membrane by interactions with the fourth repeat of spectrin ␣-chain (11). MESA (the mature parasite-infected erythrocyte surface antigen) binds to the 30-kDa domain of protein 4.1R and displaces the host protein p55 (12, 13). Its role in parasite biology is still uncertain, but interference with MESA binding is lethal to the parasite (14). The P. falciparum erythrocyte membrane protein 3 (PfEMP3), with which we are concerned here, is a large protein of 315 kDa that is expressed from the late ring stage onward and is exported via the Maurer's clefts, vesicular structures of parasite origin, into the cytoplasm of the red cell, where it associates with membrane skeleton. H...

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“…(3-Spectrin Kissimmee has an Arg instead ofa Trp at codon 202 in the N-terminal domain I, a change that affects protein 4.1 binding, not tetramerization (40). (3-Spectrin Kissimmee appears to be produced at normal levels, but the protein is abnormally sensitive to oxidation (45). Thus, ja in the mouse is the only mutation yet known that permits assessment of message stability and message usage in various tissues.…”

Section: Discussionmentioning

confidence: 99%

The murine mutation jaundiced is caused by replacement of an arginine with a stop codon in the mRNA encoding the ninth repeat of beta-spectrin.

Bloom

Kaysser

Birkenmeier

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

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The jaundiced, ja/ja, mouse mutant has a severe hemolytic anemia associated with a decency of 1&spec-trin In erythrocyte ghosts. Genes for the di phenotype and j-spectrin colocalize on Chromosome 12. «-Spectrin mRNA is not detected in reticulocytes or in brain from newborn mutant mice. To locate the nucleotide sequence alteration, the erythroid I-spectrin transcript from mutant spleen was amplified by reverse transcription PCR and sequenced. A C-to-T alteration is present in the mutant t ipt and produces a premature stop codon from an argnine codon in mRNA ending repeat 9 of (-specstrin at amino acid position 1160. The point mutation introduces a Dde I site that is present in PCR-ampllIled DNA ofja/ja andja/+ mice but not of +/+ control mice from the strain of origin, 129/Sv, or from the two strains, WB/Re and C57BL/6J, in which the mutation has been fixed by over 53 generations of backcrosslng. The genetic data confirm that the point mutation is responsible for the severe reductions in

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Abnormal oxidant sensitivity and beta-chain structure of spectrin in hereditary spherocytosis associated with defective spectrin-protein 4.1 binding.

Cited by 46 publications

References 65 publications

Beta spectrin kissimmee: a spectrin variant associated with autosomal dominant hereditary spherocytosis and defective binding to protein 4.1.

Beta spectrin kissimmee: a spectrin variant associated with autosomal dominant hereditary spherocytosis and defective binding to protein 4.1.

Plasmodium falciparum Erythrocyte Membrane Protein 3 (PfEMP3) Destabilizes Erythrocyte Membrane Skeleton

The murine mutation jaundiced is caused by replacement of an arginine with a stop codon in the mRNA encoding the ninth repeat of beta-spectrin.

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