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

• Published in: Nature communications Vol. 8; no. 1; pp. 1908 - 13
• Main Authors: Conrad, Karen S., Cheng, Ting-Wen, Ysselstein, Daniel, Heybrock, Saskia, Hoth, Lise R., Chrunyk, Boris A., am Ende, Christopher W., Krainc, Dimitri, Schwake, Michael, Saftig, Paul, Liu, Shenping, Qiu, Xiayang, Ehlers, Michael D.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04-12-2017; Nature Publishing Group; Nature Portfolio
• Subjects: 631/45/535/1266; 631/80/313; Abnormalities; Animals; BASIC BIOLOGICAL SCIENCES; Binding; CD36 antigen; CD36 Antigens - metabolism; Cellular structure; Cholesterol; Cholesterol - metabolism; Chromatography; Crystal structure; Crystallography, X-Ray; Data collection; Fibroblasts; Fibroblasts - metabolism; Glucosylceramidase; HEK293 Cells; Homology; Humanities and Social Sciences; Humans; Integral membrane proteins; Integrals; Lecithin; Ligands; Lipids; Lysosomal Membrane Proteins - metabolism; Mass spectrometry; Membrane trafficking; Mice; Molecular structure; multidisciplinary; Mutation; Neurophysiology; Parkinson's disease; Phosphatidylcholine; Phosphatidylcholines - metabolism; Phosphatidylserine; Phosphatidylserines - metabolism; Phospholipids; Phospholipids - metabolism; Proteins; Receptors, Scavenger - metabolism; Renal failure; Scavenger receptors; Science; Science (multidisciplinary); Scientific imaging; Structure-function relationships; Substrates; X-ray crystallography
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-017-02044-8

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 cholesterol and phosphatidylcholine. Binding of these lipids alters LIMP-2 from functioning as a glucocerebrosidase-binding monomer toward a dimeric state that preferentially binds anionic phosphatidylserine over neutral phosphatidylcholine. In cellular uptake experiments, LIMP-2 facilitates transport of phospholipids into murine fibroblasts, with a strong substrate preference for phosphatidylserine. Taken together, these biophysical and cellular studies define the structural basis and functional importance of a 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.
Lysosomal integral membrane protein-2 (LIMP-2) is a glucocerebrosidase receptor, which is linked to kidney failure and other diseases. Here the authors show that LIMP-2 is also a phospholipid receptor and present the lipid-bound structure of the LIMP-2 luminal domain dimer and discuss its lipid trafficking mechanism.