Összes szerző

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Schay Gusztáv

az alábbi absztraktok szerzői között szerepel:

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.