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

Nat Commun. 2017 Dec 4;8(1):1908. 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD36 Antigens / metabolism*
  • Cholesterol / metabolism*
  • Crystallography, X-Ray
  • Fibroblasts / metabolism
  • HEK293 Cells
  • Humans
  • Lysosome-Associated Membrane Glycoproteins / metabolism*
  • Mice
  • Phosphatidylcholines / metabolism*
  • Phosphatidylserines / metabolism*
  • Phospholipids / metabolism
  • Receptors, Scavenger / metabolism*


  • CD36 Antigens
  • Lysosome-Associated Membrane Glycoproteins
  • Phosphatidylcholines
  • Phosphatidylserines
  • Phospholipids
  • Receptors, Scavenger
  • SCARB2 protein, human
  • Scarb2 protein, mouse
  • Cholesterol