47 Erythrocyte Membrane Disorders Flashcards
The lipid bilayer comprises approximately _____% of the membrane mass
50%
Contains unesterified cholesterol and phospholipids in approximately equal amounts, with small amounts of glycolipids and phosphoinositides
TRUE OR FALSE
Mature erythrocytes are unable to synthesize fatty acids, phospholipids, or cholesterol de novo, and they depend on lipid exchange and limited phospholipid repair.
TRUE
Mature erythrocytes are unable to synthesize fatty acids, phospholipids, or cholesterol de novo, and they depend on lipid exchange and limited phospholipid repair.
lt regulates the fluidity of the membrane and is present in both leaflets
Cholesterol
Phospholipids are asymmetrically distributed
Located in the outer leaflet and play a role in plasma lipid exchange and renewal of membrane phospholipids
Phosphatidylcholine and sphingomyelin
choline phospholipids
Location in the lipid bilayer
Red cell antigens (A, B, H, and P): ________
Aminophospholipids: phosphatidylserine and phosphatidylethanolamine: ___________
Red cell antigens (A, B, H, and P): EXTERNAL
Aminophospholipids: phosphatidylserine and phosphatidylethanolamine: INTERNAL
The asymmetric distribution of phospholipids is maintained by a dynamic process involving ________that translocate the aminophospholipids to the inner and outer leaflets, respectively
Flippase (ATP11C) and Floppase enzymes
A missense mutation in the ATP11C gene on the X chromosome causes mild hemolytic anemia.
Asymmetry of the phospholipids is important for the survival of the erythrocyte because exposure of _________on the cell surface, as found in sickle cell disease and thalassemia, has several deleterious consequences
Phosphatidylserine
- It activates the coagulation cascade and may contribute to thromboses;
- it facilitates adhesion to the vascular endothelium;
- it provides a recognition signal for macrophages to phagocytose these cells; and
- it decreases the interaction of skeletal proteins with the bilayer, which destabilizes the membrane.
A calcium-dependent enzyme that mediates ATP-independent bidirectional movement of phospholipids down their concentration gradient and contributes to the maintenance of phosphatidylserine on the inner leaflet of the membrane.
Scramblase (PLSCR1)
Lipid rafts are anchored to ________ and play a role in signaling and invasion of malaria parasites
Associated with several proteins, including stomatin, flotillin-1 and flotillin-2.
Spectrin
2 classifications of membane proteins:
- Integral
- Peripheral
Embedded in the lipid bilayer, functions as transport proteins, receptors, signaling molecules, and carriers of red cell antigens
Require detergents to extract them
Integral or transmembrane proteins
Constitute the membrane skeleton and are loosely attached to the cytoplasmic face of the lipid bilayer and can be extracted by high or low salt concentrations or by high pH
Function either as structural proteins and form part of the membrane skeleton or they serve as linker proteins attaching the skeleton to the bilayer
Peripheral proteins
The most abundant and important erythrocyte transmembrane proteins
- Anion exchanger-1 (AE1)
- Glycophorins (GPs)
Other Integral Membrane Proteins:
* Rh-RhAG group of proteins
* Ion pumps and channels: omatin, aquaporin, glucose transporter-1 (GLUT-1)
* Cation and anion transporters
Encompasses 13 α-helical transmembrane segments and 1 nonhelicalsegment, all connected by hydrophilic loops.
Anion exchanger-1 (AE1)
- The short cytoplasmic tail binds cytosolic carbonic anhydrase II to form a metabolon with the transmembrane domain, enabling the exchange of HCO3− and Cl− anions
- The external surface of the transmembrane domain of AE1 carries several antigens, including Diego, I/i, and Wright blood groups.
- The N-terminal phosphorylated cytoplasmic domain serves as a major hub for protein-protein interactions; serves as the primary anchor of the glycolytic enzymemetabolon.
- Serves as the major attachment site of the membrane to the underlying skeleton through its interaction with ankyrin, which binds to spectrin
Gene ecoding anion exchanger-1 (AE1)
SLC4A1 gene previously known as band 3
The erythroid isoform is controlled by a promoter upstream of exon 1, whereas transcription of the kidney isoform is initiated from a promoter in intron 3
Responsible for most of the external negative charge of red cells glycophorins, which prevents the adherence of cells to each other and the vascular endothelium
Sialic acid
Function as receptors for Plasmodium falciparum, the most virulent malaria parasite
Glycophorins
- Carry a large number of blood group antigens, including MN, SsU, Miltenberger, En(a−), MK, and Gerbich
- GPA interacts with AE1 as part of a macromolecular complex
- GPC associates with protein 4.1R and p55, thereby providing an additional contact site between the membrane and the skeleton.
Plays a critical role in maintaining the shape and integrity of the red cell
Peripheral Membrane Proteins
SAAAP-iiinnnn
spectrin, actin, adducin, ankyrin, proteins 4.1R, 4.2, 4.9, p55
Major proteins of the erythrocyte membrane skeleton which interact in a horizontal plane
Spectrin, actin, proteins 4.1R, 4.2, 4.9, p55, and the adducins
Mediate the vertical attachment of the skeleton to integral membrane proteins in the lipid bilayer
Linker proteins
* Ankyrin
* Protein 4.1R
The primary connecting protein which links β- spectrin to the cytoplasmic domain of AE1, as well as to the Rh/RhAG complex
Ankyrin
Protein 4.1R binds to GPC and AE1, which serves as a secondary attachment site of the skeleton to integral membrane proteins
Major constituent of the erythrocyte membrane skeleton
Spectrin
Provides the red cell with elasticity and durability to withstand the shear stress encountered in the circulation
Other functions:
* Maintain the biconcave disk shape of the red cell
* Regulate the lateral mobility of integral membrane proteins, and
* Provide structural support for the lipid bilayer
Spectrin
Composed of 2 homologous, but structurally distinct, subunits, α and β, encoded by separate genes, SPTA1 and SPTB, respectively
Behaves like a reversible spring, which may contribute to the elasticity of the membrane
Ankyrin
- Bind to AE1 and the Rh–RhAG macromolecular complex
- Encoded by the ANK1 gene
Responsible for binding to the cytoplasmic domains of AE1 and GPC, as well as to p55, thereby linking the skeleton to the lipid bilayer
Protein 4.1R
Encoded by EPB41
Form of protein 4.1R that is predominating in young erythrocytes
Two forms of protein 4.1R, a and b
Protein 4.1b
A member of the transglutaminase family of proteins, but it has no enzyme activity because it lacks the critical triad of residues that form the active transglutaminase site
Protein 4.2
A calcium/calmodulin-binding phosphoprotein located at the spectrin–actin junctional complex
Also bind AE1 and GLUT-1, and thus form part of the macromolecular junctional complex linking the spectrin skeleton to the lipid bilaye
Adducin
A trimeric phosphoprotein that acts as a linker molecule by binding to the transmembrane GLUT-1
Dematin or protein 4.9
Composition of the ankyrin complex
AE1, GPA, Rh, and RhAG complex proteins
Ankyrin, protein 4.2, and several glycolytic enzymes
Composition of the distal junctional complex
AE1, GPC, GLUT-1, Rh, Kell, and XK proteins
Proteins 4.1R, actin, dematin, adducin, tropomyosin, tropomodulin, and p55.5
The membrane skeleton resembles a lattice-like network, with approximately ______% of the lipid bilayer directly laminated to the underlying skeleton
60%
The (horizontal or vertical) protein interactions are important in the maintenance of the structural integrity of the cell, accounting for the high tensile strength of the erythrocyte
Horizontal
The (horizontal or vertical) protein–protein interactions are critical in the stabilization of the lipid bilayer, preventing loss of microvesicles from the cells
Vertical
Average life span of RBCs
120 days
3 features that regulate the deformability of RBCs:
(a) the biconcave disk shape (a high ratio of surface area to cellular volume)
(b) the viscoelastic properties of the membrane (spectrin)
(c) the cytoplasmic viscosity
Characteristic of RBC that provides a high ratio of surface area to cellular volume and this excess of membrane is critical for survival of the cell
Biconcave disk shape
To prevent fragmentation of the membrane and loss of the biconcave disk shape, the structural integrity of the membrane skeleton is critical.
The horizontal interactions of the peripheral proteins of the junctional complex, mainly protein 4.1R and actin, which link the tail ends of the spectrin tetramers together, is a major determinant of membrane stability.
Cytoplasmic viscosity is determined primarily by the ____________
Intracellular hemoglobin concentration
As the mean cell hemoglobin concentration rises above _________, the viscosity increases exponentially
370 g/L
The hemoglobin concentration is critically dependent on red cell volume, which is primarily determined by the ___________
Total cation content of the cell
The red cell membrane maintains a _______ potassium, ________ sodium, and________calcium content within the cell.
High potassium
Low sodium
Very-low calcium
Extrudes 3 sodium ions in exchange for 2 potassium ions entering the red cell
Na+K+ ATPase
Calcium is pumped out of the cell by this channel
Protects the cell from deleterious effects of calcium, such as echinocytosis, membrane vesiculation, calpain activation, membrane proteolysis, and cellular dehydration
Calmodulin-activated Ca2+ ATPase
The Ca2+-activated K+ channel, also called the _____________
It causes selective loss of K+ in response to increased intracellular Ca2+
Gardos channel
Chloride and bicarbonate anions are readily exchanged through ____
AE1
Water is transported by
Aquaporin-1 (AQP1)
Vertical or Horizontal proteins
Result in destabilization of the bilayer, loss of membrane microvesicles and spherocyte formation
Vertical
Vertical or Horizontal proteins
Disrupt the skeleton resulting in defective shape recovery and elliptocytes
Horizontal
The most common cause of HE
and HPP
Functional self-association defect in α-Spectrin
Protein defect that cause “Acanthocytic” spherocytes present on blood film presplenectomy
β-Spectrin
Deficiency of _________ is the most common cause of HS in North America
Ankyrin
Deficiency is the most common cause of HS in parts of Europe and South Africa
“Pincered” spherocytes are common on blood film presplenectomy
AE1
Deficiency primarily found in Japanese patients with HS
Protein 4.2
The most common mutation is protein 4.2 Nippon, and patients may be homozygous for this mutation or compound heterozygotes with a second mutation on the other allele.
Protein defect in Ankyrin and Protein 4.2 cause
HS recessive
The stabilizing effect of the transmembrane section of AE1 on the lipid bilayer is lost, facilitating the formation of AE1-free microvesicles
SAO is caused by defect in what protein
AE1
Defect in this protein cause spiculated cells (acanthocytes and echinocytes) in addition to spherocytes.
Autosomal dominant HS
Beta spectrin
Defect in this protein cause “pincered” spherocytes
AE1
The hallmark of HS erythrocytes
Loss of membrane surface area relative to intracellular volume
TRUE OR FALSE
The spleen plays a secondary, but important, role in the pathophysiology of HS.
TRUE
The spleen plays a secondary, but important, role in the pathophysiology of HS.
Spherocytes are retained and ultimately destroyed in the spleen and this is the primary cause of the chronic hemolysis experienced by HS patients
The degree of splenic retention correlated with the reduction in the surface-area-to-volume ratio.
In approximately 75% of HS patients, inheritance is _________________
Autosomal dominant
Mutations of these genes are associated with recessive HS
α-spectrin or protein 4.2
Approximately _________ of HS patients have moderate disease
60% to 70%
The most frequent finding (50% of cases) of HS among children
No comparable data exist for adults.
Anemia
Followed by splenomegaly, jaundice, or a positive family history
