Conserved Luminal C-Terminal Domain Dynamically Controls Interdomain Communication in Sarcolipin

Area of Science:

• Muscle physiology and biophysics
• Molecular dynamics simulations
• Protein-lipid interactions

Background:

• Sarcolipin (SLN) is a key regulator of muscle Ca2+ transport by modulating SERCA pump activity.
• The conserved C-terminal domain of SLN is implicated in functional divergence, but its precise role is unclear.

Purpose of the Study:

• To elucidate the mechanistic role of SLN's C-terminal domain in its function.
• To investigate the interdomain communication between SLN's N- and C-termini.
• To explore the impact of C-terminal modifications and phosphorylation on SLN structure and dynamics.

Main Methods:

• All-atom molecular dynamics (MD) simulations of Sarcolipin (SLN) totaling 77.5 μs.
• Analysis of peptide stability, membrane association, and lipid bilayer properties.
• Mutual information analysis to assess interdomain communication within SLN.

Main Results:

• SLN's N- and C-terminal domains function in concert, with intrinsic interdomain communication.
• C-terminal deletions decrease SLN helix tilt and local lipid bilayer thickness but do not affect stability or membrane dissociation.
• Interdomain communication is abolished by specific C-terminal deletions (Tyr29-Tyr31) and altered by Thr5 phosphorylation, independent of force field or lipid composition.

Conclusions:

• The conserved C-terminus of SLN is essential for the dynamic control of its regulatory function.
• Interdomain communication between SLN's N- and C-termini is an intrinsic feature critical for its mechanism of action.
• Understanding SLN's C-terminal domain provides insights into muscle calcium homeostasis and SERCA regulation.