A successful change of circumstance: a transition state for membrane protein folding

Knowledge of the transition state is key to understanding a reaction mechanism. This vital information has been lacking for integral membrane protein folding, but now recent advances have given insight into the structure of their folding transition state. This progress has arisen through the successful translation of a classical protein engineering method, ϕ value analysis, from water-soluble proteins to the hydrophobic, membrane-embedded protein class. This review covers the transition state for the folding of α helical membrane proteins. Helix formation in the transition state correlates with sequence position and the order of transmembrane insertion into the cell membrane, showing that in vitro measurements, in entirely different conditions to natural membranes, may reflect the cellular situation.

► Structure of the transition state for the major final folding step of an α helical membrane protein. ► Transmembrane helix formation in the transition state correlates with primary sequence position. ► In vitro transition state structure studies agree with folding and insertion in vivo. ► Methods to determine membrane protein folding kinetics and thermodynamics. ► Application of ϕ value analysis to membrane protein folding.