Effects of the C‑Terminal
Tail on the Conformational
Dynamics of Human Neuronal Calcium Sensor‑1 Protein
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Abstract
Neuronal
calcium sensor-1 (NCS-1) protein has been implicated in
multiple neuronal functions by binding partners mostly through a largely
exposed hydrophobic crevice (HC). In the absence of a ligand, the
C-terminal tail (loop L3, residues D176 to V190) binds directly to
the HC pocket as a ligand mimetic, occupying the HC and regulating
its conformational stability. A recent experimental study reported
that L3 deletion resulted in global structure destabilization. However,
the influence of C-terminal tail on the conformations of NCS-1 protein
is unclear at the atomic level. In this study, we investigated the
structural properties and the conformational dynamics of wild type
NCS-1 and L3 truncation variant by extensive all-atom molecular dynamics
(MD) simulations. Our cumulative 2 μs MD simulations demonstrated
that L3 deletion increased the structural flexibility of the C-domain
and the distant N-domain. The community network analysis illustrated
that C-terminal tail truncation weakened the interdomain correlation.
Moreover, our data showed that the variant significantly disrupted
the salt bridges network and expanded simultaneously the global structure
and HC. These conformational changes caused by C-terminal tail truncation
may affect the regulation of target interactions. Our study provides
atomic details of the conformational dynamics effects of the C-terminal
tail on human wild type NCS-1