How Much Does TRPV1 Deviate from An Ideal MWC-Type Protein

Biophys J. 2024 Apr 6:S0006-3495(24)00249-2. doi: 10.1016/j.bpj.2024.04.005. Online ahead of print.ABSTRACTMany ion channels are known to behave as an allosteric protein, coupling environmental stimuli captured by specialized sensing domains to the opening of a central pore. The classic Monod-Wyman-Changeux (MWC) model, originally proposed to describe binding of gas molecules to hemoglobin, has been widely used as a framework for analyzing ion channel gating. Here we address the issue of how accurate the MWC model predicts activation of the capsaicin receptor TRPV1 by vanilloids. Taking advantage of a concatemeric design that makes it possible to lock TRPV1 in states with zero-to-four bound vanilloid molecules, we showed quantitatively that the overall gating behavior is satisfactorily predicted by the MWC model. There is however a small yet detectable subunit position effect: ligand binding to two kitty-corner subunits is 0.3-to-0.4 kcal/mol more effective in inducing opening than binding to two neighbor subunits. This difference-less than 10% of the overall energetic contribution from ligand binding-might be due to the restriction on subunit arrangement imposed by the planar membrane; if this is the case, the position effect is not expected in hemoglobin, in which each subunit is related equivalently to all the other subunits.PMID:38582967 | DOI:10.1016/j.bpj.2024.04.005
Source: Biophysical Journal - Category: Physics Authors: Source Type: research