Conformational dynamics and target-dependent myristoyl switch of calcineurin B homologous protein 3
Conformational dynamics and target-dependent myristoyl switch of calcineurin B homologous protein 3
Abstract Calcineurin B homologous protein 3 (CHP3) is an EF-hand Ca2+-binding protein involved in regulation of cancerogenesis, cardiac hypertrophy and neuronal development via interactions with sodium/proton exchangers (NHEs) and signalling proteins. CHP3 binds Ca2+ with micromolar affinity providing the basis to respond to intracellular Ca2+ signals. Ca2+ binding and myristoylation are important for CHP3 function but the underlying molecular mechanism remained elusive. Here, we show that Ca2+ binding and myristoylation independently affect conformational dynamics and functions of human CHP3. Ca2+ binding increased flexibility and hydrophobicity of CHP3 indicative of an open conformation. CHP3 in open Ca2+-bound conformation had higher affinity for NHE1 and associated stronger with lipid membranes compared to the closed Mg2+-bound conformation. Myristoylation enhanced flexibility of CHP3 and decreased its affinity to NHE1 independently of the bound ion, but did not affect its binding to lipid membranes. The data exclude the proposed Ca2+-myristoyl switch for CHP3. Instead, they document a Ca2+-independent exposure of the myristoyl moiety induced by binding of the target peptide to CHP3 enhancing its association to lipid membranes. We name this novel regulatory mechanism “target-dependent myristoyl switch”. Taken together, the interplay of Ca2+ binding, myristoylation and target binding allows for a context-specific regulation of CHP3 functions.
Fuchs Simon、Warscheid Bettina、Fakler Bernd、Drepper Friedel、Bildl Wolfgang、Heinicke Jonas Immanuel、Hansen Sierra C.、Kreutz Clemens、Mymrikov Evgeny V.、Refisch Lukas、Hunte Carola、Becker Florian、Liang Shuo、Schulte Uwe
Institute of Biochemistry and Molecular Biology, ZBMZ, Faculty of Medicine, University of FreiburgBiochemistry and Functional Proteomics, Institute of Biology II, Faculty of Biology, University of Freiburg||CIBSS - Centre for Integrative Biological Signalling Studies, University of Freiburg||Department of Biochemistry, Theodor-Boveri-Institute, University of W¨1rzburgInstitute for Physiology, Faculty of Medicine, University of Freiburg||CIBSS - Centre for Integrative Biological Signalling Studies, University of Freiburg||BIOSS Centre for Biological Signalling Studies, University of FreiburgBiochemistry and Functional Proteomics, Institute of Biology II, Faculty of Biology, University of FreiburgInstitute for Physiology, Faculty of Medicine, University of FreiburgInstitute of Biochemistry and Molecular Biology, ZBMZ, Faculty of Medicine, University of FreiburgInstitute of Biochemistry and Molecular Biology, ZBMZ, Faculty of Medicine, University of FreiburgInstitute of Medical Biometry and Statistics (IMBI), Faculty of Medicine and Medical Center, University of Freiburg||CIBSS - Centre for Integrative Biological Signalling Studies, University of FreiburgInstitute of Biochemistry and Molecular Biology, ZBMZ, Faculty of Medicine, University of Freiburg||CIBSS - Centre for Integrative Biological Signalling Studies, University of FreiburgInstitute of Medical Biometry and Statistics (IMBI), Faculty of Medicine and Medical Center, University of Freiburg||Institute of Physics, University of FreiburgInstitute of Biochemistry and Molecular Biology, ZBMZ, Faculty of Medicine, University of Freiburg||CIBSS - Centre for Integrative Biological Signalling Studies, University of Freiburg||BIOSS Centre for Biological Signalling Studies, University of FreiburgInstitute of Biochemistry and Molecular Biology, ZBMZ, Faculty of Medicine, University of Freiburg||Faculty of Biology, University of FreiburgInstitute of Biochemistry and Molecular Biology, ZBMZ, Faculty of Medicine, University of FreiburgInstitute for Physiology, Faculty of Medicine, University of Freiburg||CIBSS - Centre for Integrative Biological Signalling Studies, University of Freiburg||BIOSS Centre for Biological Signalling Studies, University of Freiburg
基础医学生物化学分子生物学
CHP3tescalcincalcium ionmyristoylationmyristoyl switchNHE1conformational changestarget peptideEF-hand Ca2+-binding protein
Fuchs Simon,Warscheid Bettina,Fakler Bernd,Drepper Friedel,Bildl Wolfgang,Heinicke Jonas Immanuel,Hansen Sierra C.,Kreutz Clemens,Mymrikov Evgeny V.,Refisch Lukas,Hunte Carola,Becker Florian,Liang Shuo,Schulte Uwe.Conformational dynamics and target-dependent myristoyl switch of calcineurin B homologous protein 3[EB/OL].(2025-03-28)[2025-06-23].https://www.biorxiv.org/content/10.1101/2022.09.23.509142.点此复制
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