Abstract
The superfamily of P-loop channels includes potassium, sodium, and calcium channels, as well as TRP channels and ionotropic glutamate receptors. A rapidly increasing number of crystal and cryo-EM structures have revealed conserved and variable elements of the channel structures. Intriguing differences are seen in transmembrane helices of channels, which may include π-helical bulges. The bulges reorient residues in the helices and thus strongly affect their intersegment contacts and patterns of ligand-sensing residues. Comparison of the experimental structures suggests that some π-bulges are dynamic: they may appear and disappear upon channel gating and ligand binding. The AlphaFold2 models represent a recent breakthrough in the computational prediction of protein structures. We compared some crystal and cryo-EM structures of P-loop channels with respective AlphaFold2 models. Folding of the regions, which are resolved experimentally, is generally similar to that predicted in the AlphaFold2 models. The models also reproduce some subtle but significant differences between various P-loop channels. However, patterns of π-bulges do not necessarily coincide in the experimental and AlphaFold2 structures. Given the importance of dynamic π-bulges, further studies involving experimental and theoretical approaches are necessary to understand the cause of the discrepancy.
Highlights
Academic Editor: Tanima BoseAmong the various families of ion channels, tetrameric P-loop channels stand alone due to their large functional diversity and importance in physiology, pathophysiology, pharmacology, and toxicology [1,2,3,4,5,6]
Folding of the regions, which are resolved experimentally, is generally similar to that predicted in the AlphaFold2 models
Given the importance of dynamic π-bulges, further studies involving experimental and theoretical approaches are necessary to understand the cause of the discrepancy
Summary
Among the various families of ion channels, tetrameric P-loop channels stand alone due to their large functional diversity and importance in physiology, pathophysiology, pharmacology, and toxicology [1,2,3,4,5,6]. The P-loop channels include tetramers (glutamate receptors, TRP, and potassium channels), dimers of dimers (two-pore channels) [17], and pseudo-tetramers The latter are eukaryotic sodium and calcium channels in which large pore-forming subunit folds from a single polypeptide chain of four homologous repeats [1,2]. Location of the activation gate at the cytoplasmic part of the pore [20], location of the selectivity filter at the P-loop turn [21], and the clockwise arrangement of repeats I, II, III, and IV in the sodium channels [22] were determined by experimental studies, which included mutagenesis, electrophysiology, and analysis of drug and toxin action. The similar architecture of the pore-forming domain of different P-loop channels calls for a comparative analysis of typical representatives from different channel subfamilies Such comparison, which may provide novel structural and functional insights, is a major goal of the current review. The patterns of π-bulges do not always coincide in experimental structures and AlphaFold models
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