In silico study of CIB N-myristoylation's role in inner-ear mechanotransduction.

Abstract

Inner-ear mechanotransduction is initiated when mechanical stimuli from sound and head movements stretch tip-link protein filaments to open ion channels that trigger sensory perception. These inner-ear mechanotransduction channels are formed by transmembrane channel-like (TMC) proteins 1 and 2 in complex with calcium and integrin-binding (CIB) proteins 2 and 3. Interestingly, CIB proteins may be myristoylated at their N-terminal glycine following removal of their first methionine. This addition of a 14-carbon unsaturated fatty acid is known as N-myristoylation and may provide an anchor point that mediates association with biological membranes. However, whether this is relevant for CIB function in TMC-mediated mechanotransduction is unclear. Here, we use experimentally supported AlphaFold 2 models of full-length TMC1 and TMC2 in complex with CIB2 and CIB3 in all-atom molecular dynamics simulations aimed at understanding the functional role of CIB myristoylation in TMC activation. These simulations show that the myristoylated N-terminus of CIB facilitates association of the complex with the lipid bilayer. Similarly, an amphipathic TMC α0 helix inserts into the membrane. Close association of the complex with the lipid bilayer suggest that membrane tension might play a role in the activation of TMC/CIB complexes in the inner ear.