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

Karen S. Conrad, Ting-Wen Cheng, Daniel Ysselstein, Saskia Heybrock, Lise R. Hoth, Boris A. Chrunyk, Christopher W. am Ende, Dimitri Krainc, Michael Schwake, Paul Saftig, Shenping Liu (), Xiayang Qiu () and Michael D. Ehlers
Additional contact information
Karen S. Conrad: Medicinal Sciences, Pfizer Worldwide R&D
Ting-Wen Cheng: Neuroscience Research Unit, Pfizer Worldwide R&D
Daniel Ysselstein: Department of Neurology, Northwestern University Feinberg School of Medicine
Saskia Heybrock: Biochemical Institute, Christian-Albrechts University Kiel
Lise R. Hoth: Medicinal Sciences, Pfizer Worldwide R&D
Boris A. Chrunyk: Medicinal Sciences, Pfizer Worldwide R&D
Christopher W. am Ende: Medicinal Sciences, Pfizer Worldwide R&D
Dimitri Krainc: Department of Neurology, Northwestern University Feinberg School of Medicine
Michael Schwake: Department of Neurology, Northwestern University Feinberg School of Medicine
Paul Saftig: Biochemical Institute, Christian-Albrechts University Kiel
Shenping Liu: Medicinal Sciences, Pfizer Worldwide R&D
Xiayang Qiu: Medicinal Sciences, Pfizer Worldwide R&D
Michael D. Ehlers: Neuroscience Research Unit, Pfizer Worldwide R&D

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/s41467-017-02044-8

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