Membrane homeostasis beyond fluidity: control of membrane compressibility

Abstract

Biomembranes are complex materials composed of lipids and proteins that compartmentalize biochemistry. They are actively remodeled in response to physical and metabolic cues, as well as during cell differentiation and stress. The concept of homeoviscous adaptation has become a textbook example of membrane responsiveness. Here, we discuss limitations and common misconceptions revolving around it. By highlighting key moments in the life cycle of a transmembrane protein, we illustrate that membrane thickness and a finely regulated membrane compressibility are crucial to facilitate proper membrane protein insertion, function, sorting, and inheritance. We propose that the unfolded protein response (UPR) provides a mechanism for endoplasmic reticulum (ER) membrane homeostasis by sensing aberrant transverse membrane stiffening and triggering adaptive responses that re-establish membrane compressibility.

Keywords: homeoviscous adaptation; membrane compressibility; membrane fluidity; membrane thickness; unfolded protein response.

Figure 1

Selected biophysical membrane properties discussed in this review. A schematic representation of biophysical membrane properties (top) is shown along with experimentally and computationally determined values on model membranes and biomembranes (bottom). (A) Bulk membrane viscosity modulates rotation and lateral diffusion of lipids and proteins in biomembranes. The indicated range of values for membrane properties is based on rotation frequencies [7], diffusion rates [8., 9., 10., 11., 12.], and viscosities [13]. (B) Membrane phase separation gives rise to membrane (nano)domains differing in thickness and lipid order. Different membrane lipids and proteins partition differently between coexisting domains. The indicated ranges for membrane thickness were determined for membranes composed of only one [14] or two lipids [15], for complex rat hepatocyte membranes [16], or, via molecular dynamics simulations, for yeast organelle membranes [17]. (C) Membrane bending rigidity refers to the resistance of a biomembrane against bending and curvature. The respective bending rigidities and bending moduli are plotted below [13]. (D) Transverse membrane stiffness refers to the resistance of a bilayer to a force applied perpendicular to the membrane plane causing either bilayer compression or stretching. Typically, cholesterol can be expected to increase membrane viscosity, bending rigidity, thickness, acyl chain order, and transverse membrane stiffness in most fluid, lamellar biomembranes. Thickness compressibility and area compressibility are two closely related aspects of membrane compressibility [18]. Hence, we provide values for both thickness compressibility and area compressibility of model membranes [13] along with the area compressibility of yeast organelle membranes derived from molecular dynamics simulations [17]. Abbreviations: Chol, cholesterol; DMPC, dimyrisoylphosphatidylcholine (C14:1/C14:1 PC); DOPC, dioleoylphosphatidylcholine (C18:1/C18:1 PC); DPoPC, dipalmitoleoylphosphatidylcholine (C16:1/C16:1 PC); DPPC, dipalmitoylphosphaticylcholine (C16:0/C16:0 PC); eggPC, egg yolk isolated phosphatidylcholine; ER, endoplasmic reticulum; PM, plasma membrane; POPC sn-1-palmitoyl-sn-2-oleoylphosphatidylcholine (C16:0/C18:1 PC); TGN, trans Golgi network.

Figure I

The lipid composition and environmental factors determine membrane phase behavior. Lamellar lipid bilayers come in distinct flavors differing in lipid packing and fluidity. Lipids with long, saturated acyl chains tend to form a non-fluid gel phase (L_β) also known as solid ordered phase (S_O). Most biological membranes at physiological temperatures are in the liquid disordered phase (L_D) charaterized by a high degree of membrane fluidity with respect to lateral diffusion. Sterols can order lipid acyl chains and increase lipid packing thereby giving rise to a liquid ordered phase (L_O), which can coexist with L_D domains in the same biomembrane. Furthermore, sterols can ‘fluidize’ gel domains.

Figure 2

The homeoviscous adaptation concept and common misconceptions. (A) The homeoviscous adaptation concept as proposed in its original form [22]. Bacteria cultivated at a given temperature established a characteristic lipid composition with a defined ratio of saturated (SFA) to unsaturated (UFA) lipid acyl chains. When exposed to a sudden drop of temperature, these lipids can no longer support membrane fluidity, lipid packing increases, and the membrane solidifies. However, cold-adapted bacteria can maintain membrane fluidity in the cold due to an increased proportion of unsaturated fatty acyl chains in their membranes. (B) Membrane fluidity is only a vaguely defined term, but frequently used to refer to rotational or translational motions of membrane constituents, membrane phase behavior, lipid packing, membrane compositions, or a combination of those. Important misconceptions remain even if membrane fluidity is used to refer to only translational motions. (i) Lipid acyl chains are not the only regulators of membrane viscosity. Membrane crowding, for example, has a significant impact on bulk membrane viscosity. (ii) Membrane fluidity is not a generic property. It is distinct for different molecules (here lipids versus proteins) and affected both by the length and time-scale of observation. (iii) The formation of solid-like gel phases is often considered as being incompatible with life. Yet, a reversible formation of solid-like gel phases has been observed in bacteria and mammalian cells, while highly ordered, sphingolipid-rich, but cholesterol-poor membrane patches were structurally resolved in an hexamer of the proton pump Pma1 from yeast [35], thereby providing also structural evidence for gel domains in the plasma membrane as previously predicted based by fluorescence spectroscopy [36]. (iv) The sensory mechanism regulating the proportion of saturated and unsaturated fatty acyl chains in biomembranes does not sense membrane fluidity. The lipid saturation sensor Mga2, for example, uses a bulky tryptophan residue (purple circle) to sense a small portion of the lateral stiffness profile in the membrane (indicated by different shades of gray) and its degree of activation does not correlate with membrane fluidity [37].

Figure I

Hydrophobic mismatch affects the structure, topology, and oligomerization of integral membrane proteins. A positive hydrophobic mismatch refers to a situation where an integral membrane protein features a higher hydrophobic thickness (d_P) than the surrounding lipid bilayer (d_L). Negative hydrophobic mismatch refers to the opposite situation. The impact of hydrophobic mismatch on the structure, topology, and oligomerization of integral membrane proteins is illustrated schematically for two transmembrane helices differing in their hydrophobic thickness.

Figure 3

The cellular importance of bilayer thickness and of membrane compressibility. Membrane compressibility affects the energetic penalty associated with a hydrophobic mismatch between a membrane protein and the lipid bilayer. Aberrant thickening and transverse membrane stiffening affects diverse aspects in the life cycle of a membrane protein. (i) The insertion and extraction of membrane proteins requires membrane thinning. (ii) Membrane thickness affects the conformational dynamics of proteins, thereby the population of distinct conformations and the rate of transitioning between them. This dependency can be used to control the activity of mechano-sensitive channels. (iii) Differences in membrane thickness and membrane compressibility (indicated by springs) contribute to the sorting of membrane proteins with transmembrane helices (TMHs) of different lengths along the secretory pathway. Aberrant endoplasmic reticulum (ER) membrane stiffening would lead to missorting of membrane proteins. (iv) Diving cells have to inherit their membrane proteins. Local patches of increased membrane thickness formed by ceramides form a diffusion barrier for some, but not all membrane proteins. By this mechanism the inheritance of aging factors is controlled. Abbreviation: PM, plasma membrane.