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P 21 - Prof. Dr. Carola Hunte
Modulation of sodium/proton exchanger activity by covalent modification and protein interaction
| Prof. Dr. Carola Hunte Institut für Biochemie und Molekularbiologie Centre for Biological Signalling Studies (BIOSS), Universität Freiburg Stefan-Meier-Str. 17 79104 Freiburg Phone: +49 761 203-5279 Fax: +49 761 203-5253 |
Project Summary
Sodium/proton exchangers (NHX) are critical for the control of intracellular pH and cell volume of every cell. Their transport activity is highly regulated by pH as well as by isoform-specific cytoplasmic domains which interact with a multitude of regulatory molecules and undergo covalent modification for an integrated control of NHX during cell proliferation and differentiation and in adaptation to metabolic and physiological changes. Human NHX isoforms are linked to several diseases including epilepsy, congenital Na+ diarrhea, cardiac hypertrophy, and cancer. We functionally and structurally characterized NHX model systems to describe the regulated alternate access mechanism of ion transport. We identified interaction partners of NHE1 in vertebrate brain and established in vitro studies with recombinant proteins which proved the interaction of NHE1 with calcineurin-homologous proteins and mapped their binding site. The main goal of the project is to elucidate the mechanism and structural basis of pH dependent NHX activity and of its modulation by effector molecules and post-translational modifications. In functional and structural studies with NHE1 and selected homologs, we will characterize the distinct steps of control exerted by individual interactions and covalent modifications with emphasis on the link to Ca2+ signaling to contribute to a detailed understanding of the molecular mechanism underlying the specific regulation of sodium/proton exchangers in health and disease. | |
