PLSCR3 Human

PLSCR3 is a single-pass transmembrane protein localized to the mitochondria . It is involved in the translocation of cardiolipin (CL) at the mitochondrial membrane, which is essential for mitochondrial function and structure . The protein has a conserved calcium-binding motif, and its activity is influenced by the binding of metal ions such as Ca²⁺ and Mg²⁺ .

PLSCR3 is a critical regulator of mitochondrial structure and respiration, as well as CL transport during apoptosis . Apoptosis, or programmed cell death, is a vital process for development and tissue homeostasis. Dysregulation of apoptosis can lead to various diseases, including cancer . PLSCR3’s role in apoptosis involves the translocation of phosphatidylserine (PS) from the inner to the outer leaflet of the plasma membrane, which is recognized by macrophages for the removal of apoptotic cells .

Studies have shown that disrupting the conserved calcium-binding motif of PLSCR3 results in an inactive mutant (F258V), leading to reduced proliferative capacity and abnormal mitochondrial metabolism . Cells expressing this mutant exhibit decreased mitochondrial mass, poor respiration, and reduced sensitivity to apoptosis . In contrast, wild-type PLSCR3-transfected cells show increased mitochondrial mass, enhanced respiration, and increased sensitivity to apoptosis .

Biochemical studies have revealed that recombinant human PLSCR3 can translocate aminophospholipids such as NBD-PE and NBD-PS, but not neutral phospholipids . The binding of Ca²⁺ and Mg²⁺ to PLSCR3 triggers conformational changes essential for its phospholipid translocation activity . These metal ion-induced conformational changes are mediated by protein aggregation, which is crucial for the protein’s function .