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Dematin is newly recognized as a protein that is crucial to red blood cell (RBC) membrane integrity, and dematin’s absence in mice resulted in severe abnormalities of erythrocyte shape, membrane stability, and hemolytic anemia, Yunzhe Lu of Tufts University, Boston, and her colleagues reported in the journal Blood.
The finding indicates that dematin is the major determinant of membrane stability within the junctional protein complex.
The researchers defined the role of dematin by designing a mouse model that lacked the protein. Affected mice developed severe anemia and had abnormally shaped erythrocytes with unstable membranes.
They examined the mechanism behind erythrocyte membrane instability in the mice by using membrane protein analysis, domain mapping, electron microscopy, and dynamic deformability measurements. Although many membrane and cytoskeletal proteins remained at their normal levels, spectrin, adducin, and actin were greatly reduced in these erythrocytes. The findings indicate that dematin plays a critical role in maintaining the fundamental properties of the erythrocyte’s membrane cytoskeleton complex, the researchers wrote (Blood 2016;128:93-103).
On Twitter @maryjodales
Can these findings in the erythrocytes of genetically altered mice be extrapolated to humans?
While similar, membrane composition differs in mouse and human erythrocytes. The junctional complex contains Rh polypeptides in mice but does not in humans. Glucose transporter 1 (Glut1), which associates with dematin and the adducins in humans, is not expressed in the mature erythrocytes of mice. The authors propose a model in which adducin stabilized by dematin provides linkage to the plasma membrane via band 3; however, the relatively mild phenotype seen in the alpha adducin knockout mouse argues for additional linkages, likely via dematin.
It will be important to determine the role of dematin and the effect of its deficiency in junctional complex assembly, in regulation of membrane deformability and stability in human erythrocytes, and in the context of its identified association with Glut1. Given the importance of phosphorylation in regulation of dematin-binding function and interactions, and in light of the gross disruptive effects of dematin absence reported in the study by Ms. Lu and her colleagues, investigation of the role of dematin modification in junctional protein complex assembly, enucleation and cytoskeletal remodeling, and response to malaria invasion of the red blood cell will all represent important areas of future research.
Timothy J. Satchwell, PhD, and Ashley M. Toye, PhD, of the University of Bristol, England, made their comments in an accompanying editorial (Blood. 2016;128:11-12).
Can these findings in the erythrocytes of genetically altered mice be extrapolated to humans?
While similar, membrane composition differs in mouse and human erythrocytes. The junctional complex contains Rh polypeptides in mice but does not in humans. Glucose transporter 1 (Glut1), which associates with dematin and the adducins in humans, is not expressed in the mature erythrocytes of mice. The authors propose a model in which adducin stabilized by dematin provides linkage to the plasma membrane via band 3; however, the relatively mild phenotype seen in the alpha adducin knockout mouse argues for additional linkages, likely via dematin.
It will be important to determine the role of dematin and the effect of its deficiency in junctional complex assembly, in regulation of membrane deformability and stability in human erythrocytes, and in the context of its identified association with Glut1. Given the importance of phosphorylation in regulation of dematin-binding function and interactions, and in light of the gross disruptive effects of dematin absence reported in the study by Ms. Lu and her colleagues, investigation of the role of dematin modification in junctional protein complex assembly, enucleation and cytoskeletal remodeling, and response to malaria invasion of the red blood cell will all represent important areas of future research.
Timothy J. Satchwell, PhD, and Ashley M. Toye, PhD, of the University of Bristol, England, made their comments in an accompanying editorial (Blood. 2016;128:11-12).
Can these findings in the erythrocytes of genetically altered mice be extrapolated to humans?
While similar, membrane composition differs in mouse and human erythrocytes. The junctional complex contains Rh polypeptides in mice but does not in humans. Glucose transporter 1 (Glut1), which associates with dematin and the adducins in humans, is not expressed in the mature erythrocytes of mice. The authors propose a model in which adducin stabilized by dematin provides linkage to the plasma membrane via band 3; however, the relatively mild phenotype seen in the alpha adducin knockout mouse argues for additional linkages, likely via dematin.
It will be important to determine the role of dematin and the effect of its deficiency in junctional complex assembly, in regulation of membrane deformability and stability in human erythrocytes, and in the context of its identified association with Glut1. Given the importance of phosphorylation in regulation of dematin-binding function and interactions, and in light of the gross disruptive effects of dematin absence reported in the study by Ms. Lu and her colleagues, investigation of the role of dematin modification in junctional protein complex assembly, enucleation and cytoskeletal remodeling, and response to malaria invasion of the red blood cell will all represent important areas of future research.
Timothy J. Satchwell, PhD, and Ashley M. Toye, PhD, of the University of Bristol, England, made their comments in an accompanying editorial (Blood. 2016;128:11-12).
Dematin is newly recognized as a protein that is crucial to red blood cell (RBC) membrane integrity, and dematin’s absence in mice resulted in severe abnormalities of erythrocyte shape, membrane stability, and hemolytic anemia, Yunzhe Lu of Tufts University, Boston, and her colleagues reported in the journal Blood.
The finding indicates that dematin is the major determinant of membrane stability within the junctional protein complex.
The researchers defined the role of dematin by designing a mouse model that lacked the protein. Affected mice developed severe anemia and had abnormally shaped erythrocytes with unstable membranes.
They examined the mechanism behind erythrocyte membrane instability in the mice by using membrane protein analysis, domain mapping, electron microscopy, and dynamic deformability measurements. Although many membrane and cytoskeletal proteins remained at their normal levels, spectrin, adducin, and actin were greatly reduced in these erythrocytes. The findings indicate that dematin plays a critical role in maintaining the fundamental properties of the erythrocyte’s membrane cytoskeleton complex, the researchers wrote (Blood 2016;128:93-103).
On Twitter @maryjodales
Dematin is newly recognized as a protein that is crucial to red blood cell (RBC) membrane integrity, and dematin’s absence in mice resulted in severe abnormalities of erythrocyte shape, membrane stability, and hemolytic anemia, Yunzhe Lu of Tufts University, Boston, and her colleagues reported in the journal Blood.
The finding indicates that dematin is the major determinant of membrane stability within the junctional protein complex.
The researchers defined the role of dematin by designing a mouse model that lacked the protein. Affected mice developed severe anemia and had abnormally shaped erythrocytes with unstable membranes.
They examined the mechanism behind erythrocyte membrane instability in the mice by using membrane protein analysis, domain mapping, electron microscopy, and dynamic deformability measurements. Although many membrane and cytoskeletal proteins remained at their normal levels, spectrin, adducin, and actin were greatly reduced in these erythrocytes. The findings indicate that dematin plays a critical role in maintaining the fundamental properties of the erythrocyte’s membrane cytoskeleton complex, the researchers wrote (Blood 2016;128:93-103).
On Twitter @maryjodales
FROM BLOOD
Key clinical point: Dematin is newly recognized as a protein crucial to the integrity of red blood cell membranes.
Major finding: Dematin’s absence in mice resulted in severe abnormalities of erythrocyte shape, membrane stability, and hemolytic anemia.
Data source: Studies in a newly created mouse model designed to lack dematin.
Disclosures: The researchers had no relevant financial disclosures.
