Lysosomal integral membrane protein-2 (LIMP-2/SCARB2) contributes to endosomal and lysosomal function.  LIMP-2 deficiency is associated with neurological abnormalities and kidney failure and, as an acid glucocerebrosidase receptor, impacts Gaucher and Parkinson’s diseases.  Here we report a crystal structure of a LIMP-2 luminal domain dimer with bound lipids.  Biophysical experiments demonstrated that cholesterol and phosphatidylcholine binding alters LIMP-2 from functioning as a glucocerebrosidase-binding monomer toward a dimeric state that preferentially binds anionic phosphatidylserine liposomes over neutral phosphatidylcholine liposomes.  In cellular uptake experiments, LIMP-2 facilitates transport of phospholipids into murine fibroblasts, with a strong preference for phosphatidylserine as substrate over phosphatidylcholine. Taken together, this combination of structural, biophysical, and cellular studies define the structural basis and functional importance of a novel form of LIMP-2 for lipid trafficking.  We propose a model whereby switching between monomeric and dimeric forms allows LIMP-2 to engage distinct binding partners, a mechanism that may be shared by SR-BI and CD36, scavenger receptor proteins highly homologous to LIMP-2.<br/>

Lysosomal integral membrane protein-2 as a phospholipid receptor revealed by structural, biophysical and cellular studies

2019 Spring National Meeting

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