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

Becker, Pamela S.; Tse, William T.; Lux, Samuel E.; Forget, Bernard G.

doi:10.1172/jci116628

Cited by 61 publications

(33 citation statements)

References 26 publications

(18 reference statements)

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“…In fact, the reduction of ankyrin-band 3 connection and the phosphorylation of protein 4.1 with reduced binding to spectrin lead to spherocytosis with increased osmotic fragility. [2][3][4]44 In contrast, the increase of spectrin dimers and the abnormal erythrocyte thermal sensity lead to elliptocytosis. 2,3,6,7 In our study, the erythrocyte morphology, ie elliptocytes, the biochemical pattern, ie spectrin dimers, and the phosphorylation of a membrane protein, ie ␤-spectrin, are in agreement as demonstrated by their normalization during the remission phase.…”

Section: Discussionmentioning

confidence: 99%

Reversible erythrocyte skeleton destabilization is modulated by beta-spectrin phosphorylation in childhood leukemia

Perrotta¹,

Giudice²,

Iolascon

et al. 2001

Leukemia

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The erythrocyte skeleton plays an essential role in determining the shape and deformability of the red cell. Disruption of the interaction between components of the red cell membrane skeleton may cause loss of structural and functional integrity of the membrane. Several observations based on studies in vitro strongly suggest that phosphorylation may modify interactions between proteins, leading to a reduced affinity. In particular, increased phosphorylation of ␤-spectrin decreases membrane mechanical stability. In order to investigate the presence of membrane protein defects we investigated the erythrocyte membrane protein composition and phosphorylation in 22 children with leukemia at diagnosis and during the remission phase. Sixteen children had acute lymphoblastic leukemia (ALL), three had chronic myeloid leukemia (CML) and three had acute myeloid leukemia (AML). Ten patients (eight ALL and two CML) displayed elliptocytosis and poikilocytosis, an increase of spectrin dimers (41.8 ± 15.6) and an enhanced phosphorylation of ␤-spectrin (108 ± 15%) at diagnosis. These alterations disappeared during the remission phase. This is the first demonstration of a reversible erythrocyte membrane alteration in leukemia. Since the ␤-spectrin phosphate sites are located near the C-terminal region and close to the head of the ␤-chain that is involved in dimer-dimer interaction, we supposed that the ␤-chain phosphorylation has an effect upon the interactions between spectrin dimers, ie the tetramerization process. The weakening of this process should be responsible for the presence of elliptocytes and poikilocytes as reported in hereditary elliptocytosis and pyropoikilocytosis. Leukemia (2001) 15, 440-444.

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Section: Discussionmentioning

confidence: 99%

Reversible erythrocyte skeleton destabilization is modulated by beta-spectrin phosphorylation in childhood leukemia

Perrotta¹,

Giudice²,

Iolascon

et al. 2001

Leukemia

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“…The function of terminal regions of spectrin chains has been well defined. For example, the N terminus of the ␣ spectrin chain and the C terminus of the ␤ spectrin chain are involved in tetramerization (15,16), and the N terminus of ␤ spectrin chain is responsible for binding to actin and protein 4.1R (17,18). …”

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confidence: 99%

Structural and Functional Studies of Interaction between Plasmodium falciparum Knob-associated Histidine-rich Protein (KAHRP) and Erythrocyte Spectrin

Pei

Guo

et al. 2005

Journal of Biological Chemistry

109

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Plasmodium falciparum dramatically modifies the structure and function of the membrane of the parasitized host erythrocyte. Altered membrane properties are the consequence of the interaction of a group of exported malaria proteins with host cell membrane proteins. KAHRP (the knob-associated histidine-rich protein), a member of this group, has been shown to interact with erythrocyte membrane skeletal protein spectrin. However, the molecular basis for this interaction has yet to be defined. In the present study, we defined the binding motifs in both KAHRP and spectrin and identified a functional role for this interaction. We showed that spectrin bound to a 72-amino-acid KAHRP fragment (residues 370 -441). Among nine-spectrin fragments, which encompass the entire ␣ and ␤ spectrin molecules (four ␣ spectrin and five ␤ spectrin fragments), KAHRP bound only to one, the ␣ N-5 fragment. The KAHRP-binding site within the ␣ N-5 fragment was localized uniquely to repeat 4. The interaction of fulllength spectrin dimer to KAHRP was inhibited by repeat 4 of ␣ spectrin. Importantly, resealing of this repeat peptide into erythrocytes mislocalized KAHRP in the parasitized cells. We concluded that the interaction of KAHRP with spectrin is critical for appropriate membrane localization of KAHRP in parasitized erythrocytes. As the presence of KAHRP at the erythrocyte membrane is necessary for cytoadherence in vivo, our findings have implications for the development of new therapies for mitigating the severity of malaria infection.Malaria caused by Plasmodium falciparum is the most serious parasitic disease of humans. Clinical symptoms occur during the asexual stage of the life cycle of the parasites, at which time it multiplies within the human erythrocyte. During intraerythrocytic growth, the parasite extensively modifies the host erythrocyte resulting in alterations of morphology, mechanical properties, and adhesive properties. It is generally believed that almost all the altered properties of parasitized erythrocytes are because of the action of a group of parasite proteins that become associated with erythrocyte membrane proteins (see Refs. 1-3 for recent reviews). Well studied members of this group include the knob-associated histidine-rich protein (KAHRP), 1 P. falciparum erythrocyte membrane protein 1 (PfEMP1), the ring parasite-infected erythrocyte surface antigen (RESA), and the mature parasite-infected erythrocyte surface antigen (MESA).KAHRP, an 85-105-kDa protein that is expressed during the middle and later stages of the asexual cycle (4, 5), has been shown to be critically important for knob formation in infected erythrocytes (6). It interacts with erythrocyte skeletal proteins such as spectrin, actin, and ankyrin (7, 8) and also with erythrocyte membrane-associated parasite protein, PfEMP1 (9). PfEMP1 mediates the adhesion of parasitized erythrocytes to the vascular endothelium (10), a process strongly implicated in the pathology of cerebral malaria (11). The absence of the KAHRP protein at the erythrocyte membrane l...

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“…The repeat 17 and/or domain III mutations in humans affect spectrin tetramerization and, for the most part, transcript/protein levels are unaffected. (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).…”

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

Cited by 61 publications

References 26 publications

Reversible erythrocyte skeleton destabilization is modulated by beta-spectrin phosphorylation in childhood leukemia

Reversible erythrocyte skeleton destabilization is modulated by beta-spectrin phosphorylation in childhood leukemia

Structural and Functional Studies of Interaction between Plasmodium falciparum Knob-associated Histidine-rich Protein (KAHRP) and Erythrocyte Spectrin

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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