Molecular Biomechanics Controls Protein Mixing and Segregation in Adherent Membranes

Abstract

Cells interact with their environment by forming complex structures involving a multitude of proteins within assemblies in the plasma membrane. Despite the omnipresence of these assemblies, a number of questions about the correlations between the organisation of domains and the biomechanical properties of the involved proteins, namely their length, flexibility and affinity, as well as about the coupling to the elastic, fluctuating membrane, remain open. Here we address these issues by developing an effective Kinetic Monte Carlo simulation to model membrane adhesion. We apply this model to a typical experiment in which a cell binds to a functionalized solid supported bilayer and use two ligand-receptor pairs to study these couplings. We find that differences in affinity and length of proteins forming adhesive contacts result in several characteristic features in the calculated phase diagrams. One such feature is mixed states occurring even with proteins with length differences of 10 nm. Another feature are stable nanodomains with segregated proteins appearing on time scales of cell experiments, and for biologically relevant parameters. Furthermore, we show that macroscopic ring-like patterns can spontaneously form as a consequence of emergent protein fluxes. The capacity to form domains is captured by an order parameter that is founded on the virial coefficients for the membrane mediated interactions between bonds, which allow us to collapse all the data. These findings show that taking into account the role of the membrane allows us to recover a number of experimentally observed patterns. This is an important perspective in the context of explicit biological systems, which can now be studied in significant detail.

VAP-A intrinsically disordered regions enable versatile tethering at membrane contact sites

“…Thus, a size-mediated segregation mechanism is unlikely to occur. Akin to adhesion molecules mechanics at cell‒cell contacts (Jeppesen et al, 2001; Li et al, 2021), we propose that VAP-A IDRs behave as molecular springs that ensure its vertical flexibility to provide adaptive tethering at MCS, which would facilitate membrane‒membrane adhesion when intramembrane distance fluctuates. The model in Fig.…”

Membrane Fluctuation Model for Understanding the Effect of Receptor Nanoclustering on the Activation of Natural Killer Cells through Biomechanical Feedback

“…36 Clustering, furthermore, introduces correlations between bonds that are within the membrane lateral correlation length. 15,22 This is also reflected in the rates and the effective affinity, which are calculated in the Supporting Information for the patterns presented in Figure 1.…”

“…The kinase–phosphatase balance is thus shifted at the receptor cytodomain toward the phosphatase causing lymphocyte activation . Such exclusion by size promotes equally sized ligand–receptor constructs to group within a small confinement, further promoting clustering and increasing the number of formed bonds. , …”

“…14 Such exclusion by size promotes equally sized ligand−receptor constructs to group within a small confinement, further promoting clustering and increasing the number of formed bonds. 15,16 The relation between the ligand spatial arrangement and lymphocyte activation was studied using surfaces with controlled ligand positioning. Arrays functionalized with antibodies or their binding fragments were employed to study the activation of T cells, 17−19 where the ∼10 nm nanodot size ensures that approximately one ligand, on average, occupies a single nanodot, ensuring molecular scale control of the receptor arrangement.…”