Conformational Flexibility of Transmembrane Helices: How it Works and Where it Matters.

An increasing number of multipass and oligomeric membrane proteins is found to exist in different structural substates that represent different stages of their functional cycles. Many of their constituent transmembrane helices locally deviate from canonical α-helical structure, suggesting that their conformational flexibility is required for function and/or connected to structural conversions between functional states. Biological functions of many single-pass proteins also often depend on the substantial conformational flexibility of their transmembrane helices. Current research focuses on the types and sequence dependence of helix flexibility, its diverse functional roles, as well as its interplay with the lipid environment within a membrane. This Perspective will illustrate these issues using a number of exemplary cases, including bacteriorhodopsin, ion channels, fusogenic proteins, and intramembrane protease substrates. In addition, we will discuss some methodological aspects, including advanced hydrogen-deuterium exchange analysis that can be useful in investigating the conformational flexibility of TM-helices.