The Batten disease gene product CLN6 is a glycerophosphoglycerol epimerase that establishes S,S-BMP stereochemistry
Zhu, Z.; Xiong, J.; Maaz, I.; Matrongolo, M. J.; Ghoochani, A.; Chilkunda, C.; Peng, X.; Alur, A.; Porsen, C.; Schulz, A.; Cotman, S.; Gomez-Ospina, N.; Abu-Remaileh, M.
Show abstract
Bis(monoacylglycero)phosphate (BMP), a lysosomal phospholipid essential for lipid catabolism and cholesterol clearance, has a noncanonical S,S glycerol configuration found in no other mammalian phospholipid, a feature necessary for its stability in the lysosome. How cells invert glycerol stereochemistry to build S,S-BMP has remained unexplained since this configuration was discovered five decades ago. Here, we show that the endoplasmic reticulum-resident Batten disease protein CLN6 is a Ca2+-dependent epimerase that isomerizes glycerophosphoglycerol (GPG) from R,S-GPG to S,S-GPG. CLN6-deficient cells, mouse tissues, and patient samples predominantly contain R,S-GPG, S,R-lysophosphatidylglycerol (LPG), and R,S-BMP instead of their S,S counterparts, with a net depletion of BMP. Purified CLN6 catalyzes GPG epimerization in vitro, an activity abolished by a pathogenic substitution in its substrate-binding pocket. Consistently, exogenous S,S-GPG restores BMP synthesis and relieves lipid storage in CLN6-null cells. Our work establishes stereochemical commitment upstream of acylation, placing CLN6, CLN8, and CLN5 in sequence in BMP biosynthesis and unifying the lipid defect across these neurodegenerative disorders.
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