Human NHE1 binds full-length calcineurin with high affinity and inhibits substrate dephosphorylation
Sorg, A.; Haas, J.-S.; Heinrich, M.; Gauss, S.; Kern, B. A.; Timmermann, V.; Mymrikov, E. V.; Hunte, C.
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Calcineurin (Cn) interacts with the Na+/H+-exchanger NHE1 through its calcineurin-binding domain (NHE1-CnBD). How activation of full-length Cn influences this interaction and its functional consequences has remained unclear. Here, we quantified the interaction between full-length human Cn and NHE1-CnBD in distinct activation states using fluorescence anisotropy and quantitative size-exclusion chromatography. Ca2+/calmodulin activation increased Cn affinity for NHE1-CnBD from submicromolar to tens of nanomolar affinity and stabilized the complex. NHE1-CnBD outcompeted the immunosuppressive cyclosporin A/cyclophilin A complex for Cn binding and selectively inhibited dephosphorylation of a phosphopeptide substrate while enhancing hydrolysis of p-nitrophenyl phosphate. These findings identify NHE1 as a high-affinity, substrate-competitive Cn regulator that blocks substrate recognition rather than catalysis, providing a mechanistic framework for reciprocal regulation between Cn and NHE1.
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