Hrg. Romana Schober,
"Calcium dependent signaling and gene regulation by CRAC channels"
Calcium dependent signaling and gene regulation by CRAC channels
Sprache des Titels:
Calcium (Ca2+) plays a crucial role in many cellular processes, ranging from cell growth,
differentiation, proliferation, to cell death.
One path of calcium entry into the cell is called store-operated calcium entry (SOCE). Here the depletion of the endoplasmic reticulum (ER), triggers the activation of store-operated channels (SOCs) localized in the plasma membrane (PM). Such scenario is fulfilled by the Ca2+ release activated Ca2+ (CRAC) channel, consisting of the ER localized Ca2+ sensor STIM and the PM localized Ca2+ selective channel Orai. In my PhD thesis, I want to elucidate the initial steps of STIM1 activation, a novel STIM-Orai interaction mechanism and also how the gating of the Orai channel is regulated by STIM binding.
The first part of my thesis focuses on the Ca2+ sensor STIM1. First, we investigated the luminal STIM1 Ca2+ sensing domain of the protein. A combined approach of molecular dynamics (MD) simulations and functional data enabled us to determine the exact Ca2+ ion binding sites and the very first activation steps of the luminal STIM1 protein.
The second part of my thesis focuses on the precise gating and permeation of the highly Ca2+ selective Orai1 channel. We were able to identify specific residues within the channel that are responsible for channel activation. Further, the exact gating steps of the Orai1 pore, enabling Ca2+ flux, were elucidated with the help of MD simulations. Additional work on the Orai1 channel revealed a conformational wave across the various transmembrane helices, regulating the channel in a bidirectional way. Hence, we were able to highlight a novel gating mechanism for the Orai1 channel.
In summary, my work provides new insights into the Orai1 channel and its activation mechanism,
regulated by STIM1.