Refined views of multi-protein complexes in the erythrocyte membrane

Abstract

The erythrocyte membrane has been extensively studied, both as a model membrane system and to investigate its role in gas exchange and transport. Much is now known about the protein components of the membrane, how they are organised into large multi-protein complexes and how they interact with each other within these complexes. Many links between the membrane and the cytoskeleton have also been delineated and have been demonstrated to be crucial for maintaining the deformability and integrity of the erythrocyte. In this study we have refined previous, highly speculative molecular models of these complexes by including the available data pertaining to known protein-protein interactions. While the refined models remain highly speculative, they provide an evolving framework for visualisation of these important cellular structures at the atomic level.

Reversible host cell remodeling underpins deformability changes in malaria parasite sexual blood stages

“…For example, estimates of the level of attachment of band 3 dimers to the spectrin meshwork via ankyrin or adducin range from 50% to 70% (9). The lateral mobility of the band 3 population that is not directly linked to the membrane skeleton is also slowed because weaker interactions between the cytoplasmic domain of band 3 and the skeletal meshwork "corral" its movement.…”

“…A subpopulation of band-3 dimers connects to spectrin via ankyrin (9). Band-3 dimers also participate in a second linkage complex that involves glycophorin C. This complex is linked to the membrane skeleton via glycophorin C/protein 4.1 interactions as well as band-3/adducin interactions.…”

“…This work provides fundamental insights into the molecular changes that underpin gametocyte survival in the circulation. the spectrin heterodimers are linked into junctional complexes containing actin oligomers (each with 14-16 protomers), protein 4.1R, adducin, and accessory proteins (9). Flexible linkages between the triple-helical segments of spectrin heterodimers, as well as tetramer dissociation, and breakable linkages into the junction points, are assumed to accommodate the distortions imposed by shear forces in the circulation.…”

A new junctional hierarchy

“…2 Under current transplant approaches, single-locus mismatch at HLA-A, HLA-B, HLA-C, or HLA-DRB1 is associated with increased risk of severe acute graft-versushost disease (GVHD) and mortality. 3 Additionally, mismatch at HLA-DQ confers additional risk for GVHD, and growing evidence supports that certain HLA-DPB1 mismatches increase mortality. Several efforts are underway to mitigate these risks.…”

“…In the years since, many fine studies have expanded our knowledge of the additional protein components that reside at these 2 sites, giving rise to the concepts of the familiarly depicted "ankyrin-based" and "junctional" complexes that are vital for red cell membrane structure and function. 2,3 Although evidence of the role of ankyrin in mediating vertical connectivity between spectrin and band 3 within the plasma membrane accumulated and is now well established, the concept that protein 4.1 via interaction with GPC alone performs this role within the junctional complex has remained relatively unchallenged in spite of the absent spherocytic phenotype one would expect associated with GPC deficiency. 4 More recently, a role for adducin in mediating membrane cytoskeletal connectivity at the site of the junctional complex has been proposed based on an identified interaction of this protein with band 3 5 and the presentation of mild spherocytosis in a adducin knockout mice.…”