αI-spectrin represents evolutionary optimization of spectrin for red blood cell deformability

Abstract

Spectrin tetramers of the membranes of enucleated mammalian erythrocytes play a critical role in red blood cell survival in circulation. One of the spectrins, aI, emerged in mammals with enucleated red cells after duplication of the ancestral a-spectrin gene common to all animals. The neofunctionalized aI-spectrin has moderate affinity for bI-spectrin, whereas aIIspectrin, expressed in nonerythroid cells, retains ancestral characteristics and has a 10-fold higher affinity for bI-spectrin. It has been hypothesized that this adaptation allows for rapid make and break of tetramers to accommodate membrane deformation. We have tested this hypothesis by generating mice with high-affinity spectrin tetramers formed by exchanging the site of tetramer formation in aI-spectrin (segments R0 and R1) for that of aII-spectrin. Erythrocytes with aIIbI presented normal hematologic parameters yet showed increased thermostability, and their membranes were significantly less deformable; under low shear forces, they displayed tumbling behavior rather than tank treading. The membrane skeleton is more stable with aIIbI and shows significantly less remodeling under deformation than red cell membranes of wild-type mice. These data demonstrate that spectrin tetramers undergo remodeling in intact erythrocytes and that this is required for the normal deformability of the erythrocyte membrane. We conclude that aI-spectrin represents evolutionary optimization of tetramer formation: neither higher-affinity tetramers (as shown here) nor lower affinity (as seen in hemolytic disease) can support the membrane properties required for effective tissue oxygenation in circulation.

Membrane skeleton hyperstability due to a novel alternatively spliced 4.1R can account for ellipsoidal camelid red cells with decreased deformability

“…The membrane skeleton undergoes rearrangement through repeated dissociation and reassociation of spectrin tetramers and dimers, respectively, enabling the RBC membrane to accommodate shear stress-induced distortion in the circulation ( 27 , 37 , 38 ). Prolonged membrane skeleton rearrangement with a subsequent deformed configuration precludes the recovery to the biconcave shape and results in the formation of irreversibly deformed RBCs, such as sickled cells and elliptocytes in HE ( 4 , 5 , 26 , 27 ).…”

A Systematic Compilation of Human SH3 Domains: A Versatile Superfamily in Cellular Signaling

“…The spectrin domain is a key structural component that provides mechanical stability to the cytoskeleton. It forms a long, flexible rod-like structure that can interact with other proteins, cytoskeletal elements, and lipids to provide support and resistance against deformation [ 205 , 206 , 207 ]. The SH3 domain, on the other hand, plays a key role in cytoskeletal organization and cell adhesion by regulating protein–protein interactions and localization.…”

Plasmodium falciparum selectively degrades α-spectrin of infected erythrocytes after invasion

“…Remodeling of the EMS changes the erythrocyte shape from biconcave to spherical, affecting intracellular development, proliferation, and transportation of nutrients and metabolites ( 2 , 3 ). Spectrin, a major component of the EMS, is a long, flexible, worm-like protein with α- and β-spectrin as the main components ( 4 – 6 ). The erythrocyte cytoskeleton is primarily composed of two complexes, the ankyrin complex and the actin junctional complex, which serve as scaffolds for a network of α/β-spectrin heterodimers that contribute to the shape and deformability of erythrocytes ( 7 – 10 ).…”