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; Michael D. Ehlers

doi:10.1038/s41467-017-02044-8

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, Michael D. Ehlers

^*Corresponding author for this work

Neurology

Research output: Contribution to journal › Article › peer-review

31 Scopus citations

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.

Original language	English (US)
Article number	1908
Journal	Nature communications
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-02044-8
State	Published - Dec 1 2017

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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Conrad, K. S., Cheng, T. W., Ysselstein, D., Heybrock, S., Hoth, L. R., Chrunyk, B. A., Am Ende, C. W., Krainc, D., Schwake, M., Saftig, P., Liu, S., Qiu, X., & Ehlers, M. D. (2017). Lysosomal integral membrane protein-2 as a phospholipid receptor revealed by biophysical and cellular studies. Nature communications, 8(1), [1908]. https://doi.org/10.1038/s41467-017-02044-8

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

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.",

author = "Conrad, {Karen S.} and Cheng, {Ting Wen} and Daniel Ysselstein and Saskia Heybrock and Hoth, {Lise R.} and Chrunyk, {Boris A.} and {Am Ende}, {Christopher W.} and Dimitri Krainc and Michael Schwake and Paul Saftig and Shenping Liu and Xiayang Qiu and Ehlers, {Michael D.}",

note = "Funding Information: We thank Dr Herman Overkleeft and Dr Johannes Aerts for providing their batch of MDW941 probe. We thank Katherine Hales for her assistance in image analysis, Laura J. Byrnes for assistance with negative stain EM, Johann Groth for performing in cellulo cross-linking and Kieran G. Geoghegan for proofreading the manuscript. This work was supported through grants from the Deutsche Forschungsgemeinschaft to P.S. (GRK1459) and M.S. (GRK1459 and a Heisenberg Fellowship), grant from US NIH to D.K. (R01NS076054). Publisher Copyright: {\textcopyright} 2017 The Author(s).",

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doi = "10.1038/s41467-017-02044-8",

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AU - Conrad, Karen S.

AU - Cheng, Ting Wen

AU - Ysselstein, Daniel

AU - Heybrock, Saskia

AU - Hoth, Lise R.

AU - Chrunyk, Boris A.

AU - Am Ende, Christopher W.

AU - Krainc, Dimitri

AU - Schwake, Michael

AU - Saftig, Paul

AU - Liu, Shenping

AU - Qiu, Xiayang

AU - Ehlers, Michael D.

N1 - Funding Information: We thank Dr Herman Overkleeft and Dr Johannes Aerts for providing their batch of MDW941 probe. We thank Katherine Hales for her assistance in image analysis, Laura J. Byrnes for assistance with negative stain EM, Johann Groth for performing in cellulo cross-linking and Kieran G. Geoghegan for proofreading the manuscript. This work was supported through grants from the Deutsche Forschungsgemeinschaft to P.S. (GRK1459) and M.S. (GRK1459 and a Heisenberg Fellowship), grant from US NIH to D.K. (R01NS076054). Publisher Copyright: © 2017 The Author(s).

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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.

AB - 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.

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

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