Force Transduction in the NOMPC Mechanosensitive Channel

Abstract

The recent structure of the NOMPC mechanosensitive channel, responsible for hearing and touch in fly, provides a great opportunity to understand how external mechanical forces are converted into electrical impulses through the opening of ion channels in sensory cells. NOMPC is a homo-tetramer composed of a transmembrane domain containing the ion channel pore and a cytoplasmic domain made up of 4 helical chains of 150 Å length. The chains made of 29 Ankyrin repeats come into contact with each other at two points and associate with microtubules. The transmission of external forces responsible for NOMPC gating is believed to occur by tethering the Ankyrin chains to microtubules. Previous work has demonstrated that isolated Ankyrin chains behave as biological springs under extension. Here, we combine full-atom molecular dynamics simulations, normal mode analysis (NMA), and continuum mechanics to characterize the material properties of the chains under extreme compression and extension. The NMA reveals that the lowest energy modes correspond to 4-fold symmetric compression/extension along the long-axis of the channel parallel to the membrane normal, while higher energy modes correspond to symmetric displacements of the TRP domain in the channel. The finite element model reveals that the Ankyrin chains behave as a soft spring with a linear restoring force of ∼4 pN/nm for deflections ≤15 Å, and as a non-linear spring for larger deformations. Detailed force-balance analysis on the chains during compression reveal that they exert a clockwise twisting moment on the TRP domain when viewed from the cytoplasm, which is solely a consequence of the bundle geometry. This rotation of the TRP domain is consistent with the gating mechanism suggested for the closely related TRPV1 ion channel based on open and closed structure.