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The Complex Conformational Dynamics of Neuronal Calcium Sensor-1: A Single Molecule Perspective
Dhawal Choudhary1,2, Birthe B Kragelund3, Pétur O Heidarsson4
1Department of Physics, Informatics and Mathematics, University of Modena and Reggio Emilia, Modena, Italy.
Frontiers in Molecular Neuroscience
|January 9, 2019
Summary
Human neuronal calcium sensor-1 (NCS-1) protein dynamics are crucial for neuronal function. Single-molecule studies reveal ion-binding regulates NCS-1 folding and misfolding, impacting neuronal health and disorders like autism.
Area of Science:
- Neuroscience
- Biochemistry
- Biophysics
Background:
- Human neuronal calcium sensor-1 (NCS-1) is a key EF-hand protein in neurons.
- NCS-1 regulates vital neuronal functions including neurotransmitter release and outgrowth.
- NCS-1 dysfunction is implicated in neurological disorders such as autism.
Purpose of the Study:
- To investigate the single-molecule folding and misfolding mechanisms of non-myristoylated NCS-1.
- To elucidate the role of divalent ion binding (Ca2+ and Mg2+) in NCS-1 conformational dynamics.
- To compare NCS-1 conformational equilibria with calmodulin (CaM).
Main Methods:
- Single-molecule manipulation using optical tweezers.
- Investigation of conformational equilibria across Ca2+-bound, Mg2+-bound, and apo states.
- Analysis of protein folding, misfolding pathways, and energy landscapes.
Main Results:
- NCS-1 exhibits a complex folding mechanism with a rugged energy landscape.
- Divalent ion binding (Ca2+, Mg2+) tightly regulates molecular rearrangements and energetics.
- Pathological Ca2+ concentrations can induce non-productive misfolding pathways, leading to kinetically trapped states.
Conclusions:
- Ion-regulated conformational dynamics are central to NCS-1 function.
- Misfolding events and inter-domain interactions significantly shape NCS-1's energy landscape and biological activity.
- Differences in conformational equilibria between NCS-1 and CaM are attributable to their structural properties.
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