Mechanisms of protein assembly at the membrane: Insights from theory and reaction-diffusion simulation

Margaret E. Johnson (Johns Hopkins University)

Membrane targeting and assembly of proteins is required for vesicle trafficking and receptor mediated signaling, but the extent to which the proteins recruited to these events may have evolved to exploit the 2D surface for assembly, versus pre-assembling in solution, is not known. Through theory and simulation, we have found that for a large majority of membrane targeting proteins, surface recruitment dramatically enhances their effective binding strength and subsequent complex formation. The membrane both reduces the search space and induces a cooperative binding effect for stabilizing complexes with multiple lipid binding sites. We show that the magnitude of enhancement has a simple functional form that applies whenever lipid recruiter concentrations are sufficiently high, and surprisingly, is independent of the protein binding strength. We propose that membrane localization works as a mechanism that ensures assembly only at specific times (after recruitment to surfaces) but does not precisely regulate the proteins involved, since they benefit equally from surface restriction. This robust strategy is employed by adaptor proteins involved in clathrin-mediated endocytosis in both yeast and mammalian cells, where their relatively weak binding interactions with one another prevents protein coat assembly in solution, but transitions to rapid assembly on the plasma membrane. Proteins targeting internal organelles, however, often receive limited or no benefit from membrane recruitment, indicating alternative mechanisms must control the timing of protein assembly. Our results provide simple formulas for quantifying how the ratio of membrane to solution, both in vitro and in vivo, can change the observed protein-protein interaction strengths of peripheral membrane proteins by orders of magnitude. Our numerical results were obtained using novel algorithms derived in our group for simulating reactions between diffusing proteins at single-particle resolution. In addition to the work discussed here, these simulation tools will be useful in establishing why and how assembly occurs in a wide range of processes such as cytoskeletal assembly and transcription initiation.

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