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

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Titel
Lysosomal integral membrane protein-2 as a phospholipid receptor revealed by biophysical and cellular studies
Verfasser
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.
Enthalten in
Nature Communications, Jg. 8 H. 1
Erschienen
2017
Sprache
Englisch
Dokumenttyp
Aufsatz in einer Zeitschrift
URN
urn:nbn:de:0070-pub-29533334
DOI
10.1038/s41467-017-02044-8

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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.

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