Human Neuronal Calcium Sensor-1 Protein Avoids Histidine Residues To Decrease pH Sensitivity.

Area of Science:

• Neuroscience
• Biochemistry
• Structural Biology

Background:

• Neuronal Calcium Sensor-1 (NCS-1) is crucial for synaptic function and interacts with various proteins.
• Mammalian central nervous systems maintain tight pH regulation, influencing protein conformation.
• Evolutionary differences in NCS-1, particularly the absence of histidine at key positions in humans, suggest functional importance.

Purpose of the Study:

• To investigate the impact of introducing histidine residues at positions 102 and 83 in human NCS-1.
• To analyze the effects of these mutations on protein structure, dynamics, and stability under varying pH conditions.
• To understand the evolutionary implications of histidine placement in NCS-1.

Main Methods:

• All-atom molecular dynamics simulations were employed.
• Simulations covered 5 microseconds, examining mutations R102H, S83H, R102H (protonated), and S83H (protonated).
• Community network analysis was used to assess inter- and intradomain communication.

Main Results:

• The R102H mutation increased loop L2 flexibility; R102H (protonated) decreased overall protein stability.
• Mutations R102H and S83H altered communication pathways, weakening interdomain and strengthening intradomain interactions.
• While secondary structures remained similar, global stability and salt-bridge probabilities decreased in S83H mutants.

Conclusions:

• Histidine substitutions at positions 102 and 83 affect NCS-1's local flexibility and global stability.
• Protonated histidine significantly reduces NCS-1 stability.
• The presence of histidine at these positions may be incompatible with NCS-1 function in synaptic processes due to pH sensitivity.