Identifying Optimal Lipid Raft Characteristics Required To Promote Nanoscale Protein-Protein Interactions on the Plasma Membrane

Abstract

The dynamic lateral segregation of signaling proteins into microdomains is proposed to facilitate signal transduction, but the constraints on microdomain size, mobility, and diffusion that might realize this function are undefined. Here we interrogate a stochastic spatial model of the plasma membrane to determine how microdomains affect protein dynamics. Taking lipid rafts as representative microdomains, we show that reduced protein mobility in rafts segregates dynamically partitioning proteins, but the equilibrium concentration is largely independent of raft size and mobility. Rafts weakly impede small-scale protein diffusion but more strongly impede long-range protein mobility. The long-range mobility of raft-partitioning and raftexcluded proteins, however, is reduced to a similar extent. Dynamic partitioning into rafts increases specific interprotein collision rates, but to maximize this critical, biologically relevant function, rafts must be small (diameter, 6 to 14 nm) and mobile. Intermolecular collisions can also be favored by the selective capture and exclusion of proteins by rafts, although this mechanism is generally less efficient than simple dynamic partitioning. Generalizing these results, we conclude that microdomains can readily operate as protein concentrators or isolators but there appear to be significant constraints on size and mobility if microdomains are also required to function as reaction chambers that facilitate nanoscale protein-protein interactions. These results may have significant implications for the many signaling cascades that are scaffolded or assembled in plasma membrane microdomains.

Lipid rafts: contentious only from simplistic standpoints

“…Could the type of nanoscale domains proposed here realize this function? A recent computational modelling study of raft-protein dynamics provides some preliminary answers to these questions 49 . This study considered a classic raft model in which proteins dynamically partition into rafts.…”

“…Although the effect of raft instability per se was not investigated, the average residence time of a protein in a raft was <0.1 ms. So, although the simulations of protein dynamics were based on a model of stable raft domains, the conclusion is that transient, short-lifetime protein interactions with small lipid-raft domains might still facilitate useful biochemical reactions 49 .…”

Ras proteins: paradigms for compartmentalised and isoform-specific signalling

“…Ras proteins represent an important model system because localisation has been characterised at such a high resolution and using a variety of complementary techniques. Modelling indicates that whilst Ras signalling domains are tiny (<15 nm) and occupancy in these domains is short lived (<75 μs) they can still act as protein concentrators facilitating protein-protein interactions [81]. New techniques enabling direct observation of protein dynamics within these domains are needed to validate these models however they do provide a framework for designing new experimental protocols and equipment with sufficient resolution.…”

Agonist treatment did not affect association of mu opioid receptors with lipid rafts and cholesterol reduction had opposite effects on the receptor-mediated signaling in rat brain and CHO cells

“…Caveolae are relatively large immobile raft domains with a diameter of 65 nm that can occupy 4-35% of the plasma membrane depending on cell type (Parton, 2003), whereas non-caveolae rafts, at least those occupied by GPI-anchored proteins, are mobile and smaller with a diameter less than 10 nm (Sharma et al, 2004). According to a recent simulation study, segregating proteins in caveolae vs. non-caveolae rafts was predicted to have quite different functional consequences (Nicolau et al, 2006). In both systems, however, cholesterol is an important factor for organizing signaling molecules in lipid rafts, at least opioid receptors and G proteins.…”