The physical state of lipid substrates provides transacylation specificity for tafazzin

• Published in: Nature chemical biology Vol. 8; no. 10; pp. 862 - 869
• Main Authors: Schlame, Michael, Acehan, Devrim, Berno, Bob, Xu, Yang, Valvo, Salvatore, Ren, Mindong, Stokes, David L, Epand, Richard M
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.10.2012; Nature Publishing Group
• Subjects: 1-Acylglycerophosphocholine O-Acyltransferase - metabolism; 631/92/173; 631/92/287; 631/92/314; Acylation; Aggregates; Animals; Biochemical Engineering; Biochemistry; Bioorganic Chemistry; Cell Biology; Chemistry; Chemistry and Materials Science; Chemistry/Food Science; Drosophila; Drosophila Proteins - metabolism; Drug therapy; Lipid Bilayers; Lipid Metabolism; Lipids; Micelles; Mitochondria; Nuclear Magnetic Resonance, Biomolecular; Prototypes; Substrate Specificity; Substrates
• ISSN: 1552-4450; 1552-4469
• DOI: 10.1038/nchembio.1064

Tafazzin, the mitochondrial transacylase that is deficient in Barth syndrome, selects lipid substrates in the inverted hexagonal phase but does not react with bilayer lipids. Cardiolipin is a mitochondrial phospholipid with a characteristic acyl chain composition that depends on the function of tafazzin, a phospholipid-lysophospholipid transacylase, although the enzyme itself lacks acyl specificity. We incubated isolated tafazzin with various mixtures of phospholipids and lysophospholipids, characterized the lipid phase by 31 P-NMR and measured newly formed molecular species by MS. Substantial transacylation was observed only in nonbilayer lipid aggregates, and the substrate specificity was highly sensitive to the lipid phase. In particular, tetralinoleoyl-cardiolipin, a prototype molecular species, formed only under conditions that favor the inverted hexagonal phase. In isolated mitochondria, <1% of lipids participated in transacylations, suggesting that the action of tafazzin was limited to privileged lipid domains. We propose that tafazzin reacts with non–bilayer-type lipid domains that occur in curved or hemifused membrane zones and that acyl specificity is driven by the packing properties of these domains.