Structure of human Na+/H+ exchanger NHE1 regulatory region in complex with calmodulin and Ca2+ |
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Authors: | Köster Stefan Pavkov-Keller Tea Kühlbrandt Werner Yildiz Özkan |
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Affiliation: | Department of Structural Biology, Max Planck Institute of Biophysics, Max-von-Laue Str. 3, 60438 Frankfurt am Main, Germany. |
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Abstract: | The ubiquitous mammalian Na+/H+ exchanger NHE1 has critical functions in regulating intracellular pH, salt concentration, and cellular volume. The regulatory C-terminal domain of NHE1 is linked to the ion-translocating N-terminal membrane domain and acts as a scaffold for signaling complexes. A major interaction partner is calmodulin (CaM), which binds to two neighboring regions of NHE1 in a strongly Ca2+-dependent manner. Upon CaM binding, NHE1 is activated by a shift in sensitivity toward alkaline intracellular pH. Here we report the 2.23 Å crystal structure of the NHE1 CaM binding region (NHE1CaMBR) in complex with CaM and Ca2+. The C- and N-lobes of CaM bind the first and second helix of NHE1CaMBR, respectively. Both the NHE1 helices and the Ca2+-bound CaM are elongated, as confirmed by small angle x-ray scattering analysis. Our x-ray structure sheds new light on the molecular mechanisms of the phosphorylation-dependent regulation of NHE1 and enables us to propose a model of how Ca2+ regulates NHE1 activity. |
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Keywords: | Calcium-binding Proteins Calmodulin Cellular Regulation Crystal Structure Membrane Transport pH Regulation Sodium Proton Exchange Structural Biology |
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