FIGURE 4.

How would a mechanical code be read? (A) Schematic diagram representing four mechanical switches labelled I–IV, (Left) each switch has the potential to bind different ligands in its folded, 0 and unfolded, 1 states. (Middle) The switch pattern is shown as a binary string. (Right) The ligands decorating the switches present a “read-out” mechanism as the complexes formed will depend on the mechanical coding. (i) at low force the green, orange, and yellow ligands engage the MeshCODE on switches I, II, and IV. (ii) Contractility (shown as a blue spring) switches one domain (here domain II) from the 0 to 1 state which drives a switch in binding partners, displacing the orange ligand and recruiting the blue ligand. The overall signalling complex and read-out is altered. (iii) Further contractility switches a second domain (here domain IV) further altering the coding and the proteins that are recruited to the synaptic scaffolds. Proteins, like vinculin, which bind the unfolded state of a switch lock it in that conformation and limit its ability to refold. (B–D) A cartoon of a neuron with four synapses in different states showing hypothetical ways a mechanical code might be read. Contractility as a result of synaptic signalling causes alterations to the MeshCODE switch patterns on both sides of a stimulated synapse. (B) in the pre-synaptic terminal these switch patterns might regulate the probability of release of docked vesicles by specific switches controlling this process via a hypothetical interaction with a key regulator of synaptic firing. (C) Synaptic stimulation triggers contractility in the post-synaptic region that specifically alters the switch patterns in that stimulated synapse. The altered switch patterns create “Tags” that recruit proteins (one is shown as a blue square) specifically to that synapse that enhance long-term potentiation. Switching might also displace proteins that dampen potentiation (orange circle) which then diffuse away. (D) Future signals through that synapse can trigger additional switch pattern changes and alter the binary coding in that synapse, the protein signals recruited, etc., in a dynamic re/writable way, changing the threshold of each synapse in that neuron. These changes to the synaptic adhesions as they grow and shrink dynamically in response to stimuli form the memory trace.