Divide and Adhere

The idea that cellular membrane components are mixed in a nonrandom (i.e., spatially heterogeneous) fashion (1) and that the function of these membranes is coupled to their heterogeneity has fascinated membrane biologists and biophysicists alike for at least the past 40 years.

Several models for how lateral heterogeneity can arise have been advanced. Among these, the idea that lipids exhibit functionally important heterogeneities that have been termed clusters, compositional fluctuations, domain phases, microemulsions, motional confinements, and rafts, has received a substantial amount of interest with literally thousands of contributions over the past 15 years (2).

Again, several mechanisms have been proposed that aim to explain lipid involvement in biological membrane heterogeneity. One idea that has particularly fascinated the physical chemistry fraction among lipid-membrane enthusiasts is that cellular membrane composition is poised to be near a critical mixing/demixing (or consolute) point (3). Near this region of thermodynamic parameter space, small changes in membrane conditions have large effects, and several membrane properties are governed by universal scaling relationships, rather than molecular details of the membrane constituents. Near such a consolute point, strong segregation into coexisting phases (such as the liquid-ordered, L_o and liquid-disordered phases, L_d) does not occur. Instead, compositional fluctuations arise that lead to transient membrane regions with L_o-and L_d-phase character. The lifetime and spatial extent of such composition fluctuations depends on proximity to the critical point in thermodynamic parameter space.

A major question then: What is the mechanism that triggers changes in membrane component distribution during plasma membrane signaling events?

In this issue of the Biophysical Journal, Zhao et al. (4) identify membrane adhesion as a potential mechanism for such a trigger. In their model, mobile membrane-attached sticker molecules with either preferential L_o- or L_d-phase partitioning behavior are chosen to adhere to (and therefore become immobilized at) a solid support surface. The gain in adhesion energy through concentrating stickers in the adhesion zone works against their contribution to the free energy of mixing. The important new observation by Zhao et al. is that, in addition to redistribution of stickers, further mobile membrane components either become concentrated or depleted in the adhesion zone—dependent upon the phase-partitioning preference of the stickers if the membrane composition is close to a consolute point. The authors show that this behavior can be understood within the framework of an Ising model of a nonideal mixture that is subjected to an external field. These findings extend significantly beyond the long-known idea that cross-linking of signaling receptors via their ligands may amplify plasma membrane heterogeneity in functionally important ways (5).

The observations by Zhao et al. thus add an apparently new element to the significant body of existing work describing pattern formation (i.e., lateral segregation) in membranes containing mobile adhesion molecules (6–8). Alternative effects that are known to lead to lateral segregation in adhering membranes include steric effects contributed by membrane-bound sticker and repeller molecules that may play a crucial role in T-cell signaling (9). If stickers and repellers have opposing phase-partitioning behavior, steric effects and mixing criticality could act synergistically in amplifying lateral segregation initiated by adhesion.

The next step in testing the hypothesis following from the work of Zhao et al. would be to show that the proposed mechanism is relevant to cellular function. If nonideal lipid mixing near the critical point of an L_o-L_d miscibility gap contributes to cell signaling in adhesion zones such as the immunological synapse, it should be possible to show that lipid fluorophores with a particular phase-partitioning preference are depleted from regions of close membrane contact, whereas those probes with the opposing partitioning preference should be enriched.

While the field of membrane mixing biophysics has remained controversial, the recent development of new experimental approaches such as superresolution imaging techniques, as well as new mechanisms as the one proposed by Zhao et al., give rise to the hope that we will soon understand to what extent, and in what scenarios, lipid mixing modulates membrane function.