A structural mechanism for calcium transporter headpiece closure

Area of Science:

• Biophysics
• Structural Biology
• Molecular Dynamics

Background:

• Sarcoplasmic reticulum (SR) calcium pump (SERCA) is crucial for muscle contraction.
• Understanding SERCA's conformational dynamics is key to its function.
• Previous Förster resonance energy transfer (FRET) studies suggested dynamic differences between SERCA states.

Purpose of the Study:

• To characterize the conformational dynamics of SERCA using molecular dynamics simulations.
• To correlate structural disorder and dynamics with SERCA conformation.
• To provide a mechanistic basis for interpreting FRET measurements.

Main Methods:

• All-atoms molecular dynamics simulations of SERCA.
• Coarse-grained molecular dynamics simulations.
• Analysis of structural disorder and domain-domain interactions.
• In silico mutation studies.

Main Results:

• Dynamic motions of SERCA cytoplasmic domains decrease with decreasing domain-domain separation.
• Simulations support that open SERCA conformations are more dynamic than closed ones.
• Identified a specific N-domain loop interaction critical for the open-to-closed transition.
• Mutation of key residues disrupted this transition and headpiece closure.

Conclusions:

• SERCA conformational dynamics are well-represented by molecular dynamics simulations.
• Intramolecular FRET measurements accurately report SERCA structural changes.
• A novel structural mechanism for SERCA cytoplasmic headpiece closure has been elucidated.