Abstract
The family of P-loop channels, which play key roles in the cell physiology, is characterized by four membrane re-entering extracellular P-loops that connect eight transmembrane helices of the pore-forming domain. The X-ray and cryo-EM structures of the open- and closed-state channels show conserved state-dependent folding despite the sequences are very diverse. In sodium, calcium, TRPV and two-pore channels, the pore-lining helices contain conserved asparagines and may or may not include π-helix bulges. Comparison of the sequence- and 3D-alignemnts suggests that the asparagines appeared in evolution as insertions that are accommodated in two ways: by π-helix bulges, which preserve most of inter-segment contacts, or by twists of the C-terminal thirds and switch of inter-segment contacts. The two possibilities should be considered in homology modeling of ion channels and in structure-based interpretations of numerous experimental data on physiology, pathophysiology, pharmacology and toxicology of the channels.