Processing and Topology of the Yeast Mitochondrial Phosphatidylserine Decarboxylase 1

Abstract

Background: Although phosphatidylserine decarboxylase 1 (Psd1) is of central importance for the generation of cellular phosphatidylethanolamine (PE), its biogenesis is only poorly understood. Results: Biogenesis of Psd1 involves processing by two proteases, MPP and Oct1, and an autocatalytic separation of Psd1␣ from the membrane-anchored Psd1␤. Conclusion: Psd1 requires integration into the inner mitochondrial membrane for full enzymatic activity. Significance: This study presents a new model for the biogenesis and topology of Psd1.

Phosphatidylserine Decarboxylase 1 Autocatalysis and Function Does Not Require a Mitochondrial-specific Factor

“…PE, the second most abundant phospholipid in eukaryotes, is a precursor to phosphatidylcholine (3-6), the major membrane phospholipid. In yeast, two enzymes mediate the production of PE from PS; Psd1p located in the mitochondrion (7)(8)(9), and Psd2p, a resident of endosomes (10). Yeast without PSD1 and PSD2 cannot grow unless supplemented with ethanolamine, which feeds production of PE via the cytidine diphosphate (CDP)-ethanolamine pathway (11)(12)(13).…”

“…Upon import into the mitochondrion, the mitochondrial targeting sequence (MTS) of Psd1p is removed by the sequential action of two matrix peptidases, mitochondrial processing peptidase and Oct1p (7). Autocatalytic processing of Psd1p, an obligate step for its function (25), can occur before or after its integration into the mitochondrial inner membrane (IM) (7). Autocatalysis occurs within a conserved LGST motif between the glycine and the serine residues through a process of serinolysis (7,(25)(26)(27)(28)(29).…”

“…Autocatalytic processing of Psd1p, an obligate step for its function (25), can occur before or after its integration into the mitochondrial inner membrane (IM) (7). Autocatalysis occurs within a conserved LGST motif between the glycine and the serine residues through a process of serinolysis (7,(25)(26)(27)(28)(29). Serinolysis separates the enzyme into mature ␣ and ␤ subunits, which remain non-covalently associated, and generates a pyruvoyl prosthetic group at the NH 2 terminus of the ␣ subunit that is absolutely required for enzymatic activity (25,29,30).…”

“…Serinolysis separates the enzyme into mature ␣ and ␤ subunits, which remain non-covalently associated, and generates a pyruvoyl prosthetic group at the NH 2 terminus of the ␣ subunit that is absolutely required for enzymatic activity (25,29,30). The ␤ subunit is integrated into the IM of the mitochondrion and serves to anchor the ␣ subunit to the intermembrane space (IMS) side of the IM (7,8). Although unrelated to Psd1p activity, the amino terminus of Psd1p is necessary and sufficient to induce multidrug resistance via Pdr5p signaling in yeast (27).…”

“…Psd1p is synthesized as a zymogen and must be imported into the inner mitochondrial membrane where it is processed to achieve its functional state (7,21). Upon import into the mitochondrion, the mitochondrial targeting sequence (MTS) of Psd1p is removed by the sequential action of two matrix peptidases, mitochondrial processing peptidase and Oct1p (7).…”