Why signaling works better in 2D than 3D

What is it about?

In eukaryotic cells, the translocation of a signaling protein from the cytosol to the cell membrane will sometimes be enough to initiate downstream responses. Why translocation facilitates signaling has been a subject of lively debate, with many theoretical propositions but little experimental evidence. One such hypothesis states that intermolecular encounters are more frequent on membranes than in solution, in part because the interacting proteins are closer to each other in 2D, and in part because of the reduction of dimensionality—2D searches are more efficient than 3D searches because it's easier to go the wrong way in 3D. Although attractive, this idea has been challenged by the fact that membrane diffusion is significantly slower than cytoplasmic diffusion, which means that the proteins might actually encounter each other less frequently in the 2D membrane than they would in the 3D cytoplasm. This is a conundrum! Here Huang and colleagues show through careful quantitative experiments that the identical association reaction—the binding of complementary DNA strands to each other—should happen about 22- to 33-fold faster on 2D membranes than in 3D solution in a typically-sized eukaryotic cell. About half of the advantage comes from more frequent collisions in 2D (despite the higher viscosity of the membrane), and about half from an increase in the probability of binding after colliding. The advantage of 2D over 3D is greatly diminished in cells as small as bacteria, so this may be a eukaryotes-only strategy.

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Photo by Harpreet Singh on Unsplash

Photo by Harpreet Singh on Unsplash

Why is it important?

This work finally brings experimental evidence to bear on a decades-old question of relevance to several important signaling pathways, including the Ras-MAPK pathway, which is inappropriately activated in many human cancers, including many of the deadliest cancers (pancreatic cancer, lung cancer, colon cancer...). Now we know that 2D localization does facilitate macromolecular interaction, and we know how it does.

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