Functional lipid pairs as building blocks of phase-separated membranes

Abstract

Biological membranes exhibit a great deal of compositional and phase heterogeneity due to hundreds of chemically distinct components. As a result, phase separation processes in cell membranes are extremely difficult to study, especially at the molecular level. It is currently believed that the lateral membrane heterogeneity and the formation of domains, or rafts, are driven by lipid–lipid and lipid–protein interactions. Nevertheless, the underlying mechanisms regulating membrane heterogeneity remain poorly understood. In the present work, we combine inelastic X-ray scattering with molecular dynamics simulations to provide direct evidence for the existence of strongly coupled transient lipid pairs. These lipid pairs manifest themselves experimentally through optical vibrational (a.k.a. phononic) modes observed in binary (1,2-dipalmitoyl-sn-glycero-3-phosphocholine [DPPC]–cholesterol) and ternary (DPPC–1,2-dioleoyl-sn-glycero-3-phosphocholine/1-palmitoyl-2-oleoyl-glycero-3-phosphocholine [DOPC/POPC]–cholesterol) systems. The existence of a phononic gap in these vibrational modes is a direct result of the finite size of patches formed by these lipid pairs. The observation of lipid pairs provides a spatial (subnanometer) and temporal (subnanosecond) window into the lipid–lipid interactions in complex mixtures of saturated/unsaturated lipids and cholesterol. Our findings represent a step toward understanding the lateral organization and dynamics of membrane domains using a well-validated probe with a high spatial and temporal resolution.

Active cholesterol 20 years on

“…The absolute affinities of different membrane phospholipids for cholesterol are not known, but it has been shown that they vary over about an order of magnitude 2,21‐24 . Their complexes have stoichiometries that range from 1:1 for high‐affinity (long chain, saturated) species to two phospholipids per cholesterol for less avid lipids 3,18,20,23,25 . Sterols are more avid for sphingomyelin than for glycerophospholipids, and they favor saturated over unsaturated chains and phosphorylcholine over phosphorylserine over phosphorylethanolamine polar head groups.…”

Influence of Cholesterol Concentration on Bacteriorhodopsin Photocycle

“…On the other hand, the addition of even a small amount of cholesterol to the membrane brings about the formation of domains in it [13], whose thickness is larger than the thickness of single component membrane [20]. The arrangement of the domains around the BR molecules reduces the local difference between the thicknesses of the hydrophobic part of protein and the membrane, thus reducing the strength of the lipid-protein interaction (Fig.…”

“…Lipid membranes are an important component of living organisms, because they regulate plenty of the processes that are required to maintain the viability of every cell and cell organelles. That is why a considerable number of works on biophysics is devoted to the study of phase transitions in lipid membranes and their dependence on the temperature and pressure [1][2][3][4], the structural characteristics of various lipid phases [5,6], the influence of various impurities on the properties of membranes [7][8][9][10][11], as well as to the measurement of the dynamic characteristics of singleand multicomponent membranes [12,13].…”

Lateral heterogeneity and domain formation in cellular membranes

“…However, recent research has suggested that sphingomyelin also has strong homophilic interactions, and that cholesterol's interactions take place deeper within the membrane's acyl chain region, i.e., lower than sphingomyelin's functional amide group ( Yano et al, 2018 ). Moreover, in systems that form large domains, there is evidence of cholesterol segregating within ordered domains ( Javanainen et al, 2017 , Soloviov et al, 2020 ). Currently, it is safe to say that cholesterol's role within ordered domains remains a topic of current research and debate.…”