SPEG Controls Calcium Reuptake Into the Sarcoplasmic Reticulum Through Regulating SERCA2a by Its Second...

Area of Science:

• Molecular biology
• Cardiovascular research
• Biochemistry

Background:

• Striated muscle preferentially expressed protein kinase (SPEG) possesses two kinase domains essential for cardiac development and function.
• The specific roles of SPEG's two kinase domains in maintaining cardiac performance remain largely uncharacterized.

Purpose of the Study:

• To elucidate the distinct molecular functions of the two kinase domains within SPEG.
• To investigate the interaction and regulatory mechanisms between SPEG and its substrates in cardiac cells.

Main Methods:

• Proteomics identified SERCA2a as a binding partner for SPEG's second kinase domain.
• In vitro and cell-based assays assessed the phosphorylation of SERCA2a at Thr484 by SPEG.
• An inducible heart-specific Speg knockout mouse model was utilized to study in vivo cardiac function.

Main Results:

• SPEG's second kinase domain phosphorylates SERCA2a at Thr484, enhancing its calcium reuptake activity.
• SPEG's first kinase domain interacts with and phosphorylates junctophilin-2 (JPH2).
• In vivo Speg deletion impairs SERCA2a function, leading to cardiac dysfunction and heart failure.

Conclusions:

• The two kinase domains of SPEG exhibit distinct roles in regulating cardiac function.
• SPEG's second kinase domain is a key regulator of SERCA2a activity and cardiac calcium handling.
• Targeting SPEG could offer a novel therapeutic strategy for heart diseases characterized by calcium homeostasis disruption.