Structural and mechanical properties of the red blood cell’s cytoplasmic membrane seen through the lens of biophysics

Red blood cells (RBCs) are the most abundant cell type in the human body and critical suppliers of oxygen. The cells are characterized by a simple structure with no internal organelles. Their two-layered outer shell is composed of a cytoplasmic membrane (RBC( cm )) tethered to a spectrin cytoskeleton allowing the cell to be both flexible yet resistant against shear stress. These mechanical properties are intrinsically linked to the molecular composition and organization of their shell. The cytoplasmic membrane is expected to dominate the elastic behavior on small, nanometer length scales, which are most relevant for cellular processes that take place between the fibrils of the cytoskeleton. Several pathologies have been linked to structural and compositional changes within the RBC( cm ) and the cell’s mechanical properties. We review current findings in terms of RBC lipidomics, lipid organization and elastic properties with a focus on biophysical techniques, such as X-ray and neutron scattering, and Molecular Dynamics simulations, and their biological relevance. In our current understanding, the RBC( cm )’s structure is patchy, with nanometer sized liquid ordered and disordered lipid, and peptide domains. At the same time, it is surprisingly soft, with bending rigidities κ of 2–4 k(B)T. This is in strong contrast to the current belief that a high concentration of cholesterol results in stiff membranes. This extreme softness is likely the result of an interaction between polyunsaturated lipids and cholesterol, which may also occur in other biological membranes. There is strong evidence in the literature that there is no length scale dependence of κ of whole RBCs.