Journal Article

FZJ-2021-03098

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Thermodynamic profile of mutual subunit control in a heteromeric receptor

Schirmeyer, J. ; Hummert, S. ; Eick, T. ; Schulz, E. ; Schwabe, T. ; Ehrlich, G. ; Kukaj, T. ; Wiegand, M. ; Sattler, C. ; Schmauder, R. ; Zimmer, T. ; Kosmalla, N. ; Münch, J. ; Bonus, M. ; Gohlke, H.FZJ* ; Benndorf, K. (Corresponding author)

2021
National Acad. of Sciences Washington, DC

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Please use a persistent id in citations: http://hdl.handle.net/2128/28350  doi:10.1073/pnas.2100469118

Abstract: Cyclic nucleotide-gated (CNG) ion channels of olfactory neurons are tetrameric membrane receptors that are composed of two A2 subunits, one A4 subunit, and one B1b subunit. Each subunit carries a cyclic nucleotide-binding domain in the carboxyl terminus, and the channels are activated by the binding of cyclic nucleotides. The mechanism of cooperative channel activation is still elusive. Using a complete set of engineered concatenated olfactory CNG channels, with all combinations of disabled binding sites and fit analyses with systems of allosteric models, the thermodynamics of microscopic cooperativity for ligand binding was subunit- and state-specifically quantified. We show, for the closed channel, that preoccupation of each of the single subunits increases the affinity of each other subunit with a Gibbs free energy (ΔΔG) of ∼−3.5 to ∼−5.5 kJ ⋅ mol−1, depending on the subunit type, with the only exception that a preoccupied opposite A2 subunit has no effect on the other A2 subunit. Preoccupation of two neighbor subunits of a given subunit causes the maximum affinity increase with ΔΔG of ∼−9.6 to ∼−9.9 kJ ⋅ mol−1. Surprisingly, triple preoccupation leads to fewer negative ΔΔG values for a given subunit as compared to double preoccupation. Channel opening increases the affinity of all subunits. The equilibrium constants of closed–open isomerizations systematically increase with progressive liganding. This work demonstrates, on the example of the heterotetrameric olfactory CNG channel, a strategy to derive detailed insights into the specific mutual control of the individual subunits in a multisubunit membrane receptor.

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Contributing Institute(s):

1. Jülich Supercomputing Center (JSC)
2. John von Neumann - Institut für Computing (NIC)
3. Strukturbiochemie (IBI-7)
4. Bioinformatik (IBG-4)

Research Program(s):

1. 5111 - Domain-Specific Simulation & Data Life Cycle Labs (SDLs) and Research Groups (POF4-511) (POF4-511)
2. 2171 - Biological and environmental resources for sustainable use (POF4-217) (POF4-217)
3. 2172 - Utilization of renewable carbon and energy sources and engineering of ecosystem functions (POF4-217) (POF4-217)
4. Forschergruppe Gohlke (hkf7_20200501) (hkf7_20200501)

Appears in the scientific report 2021

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Database coverage:
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