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Liliom Károly

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Liliom Károly
Conformational dynamics of human Calmodulin under low calcium loads.

Aug 29 - kedd

15:30 – 17:00

I. Poszterszekció

P16

Conformational Dynamics of Human Calmodulin at Low Ca2+ Saturations

Gusztáv Schay1, Klaudia Onica2, Arian Jafari1, Franci Merzel3, Miklós Kellermayer1, Erika Balog1, and Károly Liliom1

1Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary

2Pázmány Péter Catholic University, Budapest, Hungary

3National Institute of Chemistry, Ljubljana, Slovenia

Calmodulin is an extremely conservative key protein of intracellular signal transduction. It can bind four Ca2+-ions by two EF-hand motifs in its N- and C-terminal domains. During Ca2+-binding hidden hydrophobic surfaces become available, which take part in recognition of a broad range of target proteins. These observations led to the idea of calmodulin being a molecular switch, activating its partners when Ca2+-saturated at elevated intracellular calcium levels. It is known that calmodulin can adopt numerous conformational states, however, the change of conformers along Ca2+-binding is not known. Importantly, considering the intracellular calmodulin and Ca2+-levels, and the Ca2+-affinities of calmodulin EF-hands, it is unlikely that calmodulin gets Ca2+-saturated in physiologic signaling conditions. What is then the mechanism of target protein selection? The Ca2+-binding of calmodulin displays cooperativity which can be described by a Perutz binding model to explain Ca2+-saturation experiments in vitro. The function/conformation of calmodulin at low Ca2+-loads has not been explored yet in details, whereas all physiologic Ca2+-signaling happens at low Ca2+/calmodulin concentration ratio. Compartmentalization of target proteins and canonic binding modes of Ca2+-saturated calmodulin cannot account for why the spatiotemporal information content of intracellular Ca2+-signaling is not lost during calmodulin signal transduction.

Our experiments uncovered an increased conformational diversity at low Ca2+/calmodulin concentration ratio, and that the binding of model peptide melittin to calmodulin happened much before the Ca2+-saturation of the protein. We carried out molecular dynamics simulations of calmodulin with adding two Ca2+-ions to the C-terminal EF-hands of apocalmodulin and also by removing two Ca2+-ions from the N-terminal EF-hands of holocalmodulin. We observed striking differences in the structural dynamics of the N-terminal apo–C-terminal holo calmodulin, depending on the initial state from which we have reached this state. Based on our experiments and molecular dynamics calculations we hypothesize that the spatiotemporal changes in intracellular Ca2+-concentrations can be coded into the structural/conformational dynamics of calmodulin.

This work was supported by the grants FK-135517, TKP2021-EGA-23, and STIA-KFI-0012.