Identification of a Novel Role for Dematin in Regulating Red Cell Membrane Function by Modulating Spectrin-Actin Interaction

Koshino, Ichiro; Mohandas, Narla; Takakuwa, Yuichi

doi:10.1074/jbc.m111.305441

Cited by 46 publications

(49 citation statements)

References 26 publications

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“…50 For instance, the phosphorylation of cytoskeletal proteins by PKA or other kinases decreases the membrane stability. [51][52][53] We propose that PKA-mediated phosphorylation of STEVOR S 324 may change the conformation of the STEVOR C-terminal domain and increase its interaction with the skeleton partner, thus increasing stiffness of the membrane. These interactions are also likely dependent on phosphorylation or other posttranslational modifications of host membrane proteins.…”

Section: Discussionmentioning

confidence: 99%

Plasmodium falciparum STEVOR phosphorylation regulates host erythrocyte deformability enabling malaria parasite transmission

Naissant

Dupuy

Duffier

et al. 2016

Blood

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Key Points• P falciparum STEVORs interact with the erythrocyte cytoskeletal ankyrin complex.• Infected erythrocyte deformability is regulated by PKA-mediated phosphorylation of STEVOR cytoplasmic domain.Deformability of Plasmodium falciparum gametocyte-infected erythrocytes (GIEs) allows them to persist for several days in blood circulation and to ensure transmission to mosquitoes. Here, we investigate the mechanism by which the parasite proteins STEVOR (SubTElomeric Variable Open Reading frame) exert changes on GIE deformability. Using the microsphiltration method, immunoprecipitation, and mass spectrometry, we produce evidence that GIE stiffness is dependent on the cytoplasmic domain of STEVOR that interacts with ankyrin complex at the erythrocyte skeleton. Moreover, we show that GIE deformability is regulated by protein kinase A (PKA)-mediated phosphorylation of the STEVOR C-terminal domain at a specific serine residue (S 324 ). Finally, we show that the increase of GIE stiffness induced by sildenafil (Viagra) is dependent on STEVOR phosphorylation status and on another independent mechanism. These data provide new insights into mechanisms by which phosphodiesterase inhibitors may block malaria parasite transmission. (Blood. 2016;127(24):e42-e53)

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Section: Discussionmentioning

confidence: 99%

Plasmodium falciparum STEVOR phosphorylation regulates host erythrocyte deformability enabling malaria parasite transmission

Naissant

Dupuy

Duffier

et al. 2016

Blood

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“…35 These studies suggested a functional role of dematin in late erythropoiesis, consistent with earlier studies on dematin expression during erythropoiesis. 26,36 Our results show that dematin functions as a negative regulator of erythroblast enucleation without affecting primitive erythropoiesis (Figure 2). This finding is consistent with the absence of nucleated erythroid precursors in the peripheral blood of FKLO mice.…”

Section: Discussionmentioning

confidence: 79%

“…This finding is consistent with a previous demonstration that dematin binds to a mini-spectrin construct containing both a and b subunits, and this interaction is sensitive to phosphorylation of dematin by cAMP-dependent protein kinase. 26 As mentioned in the previous study, 26 the biochemical interaction of dematin with actin and spectrin and its sensitivity to phosphorylation by cAMPdependent protein kinase have been previously documented. 4,17 In our study, we also noticed a significant reduction in the protein-protein interaction between spectrin and the full-length dematin-S381E mutation ( Figure 5F,G, lane 11).…”

Section: Dematin Is Essential For Rbc Membrane Integrity 97mentioning

confidence: 72%

Gene disruption of dematin causes precipitous loss of erythrocyte membrane stability and severe hemolytic anemia

Hanada

Fujiwara

et al. 2016

Blood

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• Genetic deletion of full-length mouse dematin causes severe abnormalities of erythrocyte shape, membrane stability, and hemolytic anemia.• Dematin is critical for the junctional complex integrity.Dematin is a relatively low abundance actin binding and bundling protein associated with the spectrin-actin junctions of mature erythrocytes. Primary structure of dematin includes a loosely folded core domain and a compact headpiece domain that was originally identified in villin. Dematin's actin binding properties are regulated by phosphorylation of its headpiece domain by cyclic adenosine monophosphate-dependent protein kinase.Here, we used a novel gene disruption strategy to generate the whole body dematin gene knockout mouse model (FLKO). FLKO mice, while born at a normal Mendelian ratio, developed severe anemia and exhibited profound aberrations of erythrocyte morphology and membrane stability. Having no apparent effect on primitive erythropoiesis, FLKO mice show significant enhancement of erythroblast enucleation during definitive erythropoiesis. Using membrane protein analysis, domain mapping, electron microscopy, and dynamic deformability measurements, we investigated the mechanism of membrane instability in FLKO erythrocytes. Although many membrane and cytoskeletal proteins remained at their normal levels, the major peripheral membrane proteins spectrin, adducin, and actin were greatly reduced in FLKO erythrocytes. Our results demonstrate that dematin plays a critical role in maintaining the fundamental properties of the membrane cytoskeleton complex. (Blood. 2016;128(1):93-103)

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“…These differences make non-erythrocytic spectrin more stable and erythrocyte spectrin more flexible. Except for the resolved spectrin repeat fragments, the crystal and NMR structures of the domains interacting with other proteins have also been resolved, including actin-binding [19] and pleckstrin homology domains [20] (Table 2). …”

Section: The Structure Of Spectrinmentioning

confidence: 99%

Spectrin: Structure, function and disease

Zhang

Zhao

et al. 2013

Sci. China Life Sci.

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Spectrin is a large, cytoskeletal, and heterodimeric protein composed of modular structure of and subunits, it typically contains 106 contiguous amino acid sequence motifs called "spectrin repeats". Spectrin is crucial for maintaining the stability and structure of the cell membrane and the shape of a cell. Moreover, it contributes to diverse cell functions such as cell adhesion, cell spreading, and the cell cycle. Mutations of spectrin lead to various human diseases such as hereditary hemolytic anemia, type 5 spinocerebellar ataxia, cancer, as well as others. This review focuses on recent advances in determining the structure and function of spectrin as well as its role in disease.erythrocyte, spectrin, cell cycle, mass spectrometry, disease Citation:Zhang R, Zhang C Y, Zhao Q, et al. Spectrin: Structure, function and disease.

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Identification of a Novel Role for Dematin in Regulating Red Cell Membrane Function by Modulating Spectrin-Actin Interaction

Cited by 46 publications

References 26 publications

Plasmodium falciparum STEVOR phosphorylation regulates host erythrocyte deformability enabling malaria parasite transmission

Plasmodium falciparum STEVOR phosphorylation regulates host erythrocyte deformability enabling malaria parasite transmission

Gene disruption of dematin causes precipitous loss of erythrocyte membrane stability and severe hemolytic anemia

Spectrin: Structure, function and disease

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