Title :
structure of LIMP-2 provides functional insights with implications for
SR-BI and
CD36
Abstract :
- Members of the CD36 superfamily of scavenger receptor proteins are important regulators of lipid metabolism and innate immunity
- They recognize normal and modified lipoproteins , as well as pathogen-associated molecular patterns
- The family consists of three members: SR-BI (which delivers cholesterol to the liver and steroidogenic organs and is a co- receptor for hepatitis C virus), LIMP-2 / LGP85 (which mediates lysosomal delivery of β-glucocerebrosidase and serves as a receptor for enterovirus 71 and coxsackieviruses) and CD36 (a fatty-acid transporter and receptor for phagocytosis of effete cells and Plasmodium-infected erythrocytes)
- Notably, CD36 is also a receptor for modified lipoproteins and β-amyloid, and has been implicated in the pathogenesis of atherosclerosis and of Alzheimer's disease
- Despite their prominent roles in health and disease, understanding the function and abnormalities of the CD36 family members has been hampered by the paucity of information about their structure
- Here we determine the crystal structure of LIMP-2 and infer, by homology modelling, the structure of SR-BI and CD36
- LIMP-2 shows a helical bundle where β-glucocerebrosidase binds, and where ligands are most likely to bind to SR-BI and CD36
- Remarkably, the crystal structure also shows the existence of a large cavity that traverses the entire length of the molecule
- Mutagenesis of SR-BI indicates that the cavity serves as a tunnel through which cholesterol(esters) are delivered from the bound lipoprotein to the outer leaflet of the plasma membrane
- We provide evidence supporting a model whereby lipidic constituents of the ligands attached to the receptor surface are handed off to the membrane through the tunnel, accounting for the selective lipid transfer characteristic of SR-BI and CD36