Primitive Phospholamban- and Sarcolipin-like Peptides Inhibit the Sarcoplasmic Reticulum Calcium Pump SERCA

Area of Science:

• Biochemistry
• Molecular Biology
• Evolutionary Biology

Background:

• Intracellular calcium signaling is vital, with sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) maintaining calcium homeostasis.
• SERCA is regulated by transmembrane subunits like phospholamban and sarcolipin in mammals, crucial for muscle function.
• These regulators are highly conserved across mammalian species.

Purpose of the Study:

• To investigate sequence variation tolerance in mammalian SERCA regulation by transmembrane peptides.
• To determine if divergent arthropod sarcolambans mimic phospholamban or sarcolipin regulatory activities despite sequence dissimilarity.

Main Methods:

• Expression and purification of recombinant arthropod sarcolamban peptides.
• Co-constitution of peptides with mammalian SERCA1a into proteoliposomes.
• Measurement of peptide effects on SERCA's apparent calcium affinity and maximal activity.
• Utilizing molecular modeling, protein-protein docking, and molecular dynamics simulations.

Main Results:

• All three tested arthropod sarcolambans acted as potent inhibitors of mammalian SERCA1a.
• These peptides exhibited either phospholamban-like or sarcolipin-like regulatory characteristics.
• Novel structural features and regulatory properties of these divergent peptides were revealed.

Conclusions:

• Arthropod sarcolambans can effectively regulate mammalian SERCA activity, demonstrating conserved function across vast evolutionary distances.
• Despite significant sequence divergence, these peptides retain inhibitory roles, offering insights into the evolution of calcium pump regulation.
• The findings highlight the plasticity of SERCA regulation and the ancient origins of its regulatory mechanisms.