Low-density lipoprotein receptor family (LDLR family) (LDLR family)

The low-density lipoprotein receptor (LDLR) family is a group of evolutionarily conserved cell surface receptors, including LDLR, VLDLR, ApoER2, and LRP1, that mediate the endocytosis of various ligands (UniProt P01130). These receptors are characterized by extracellular cysteine-rich repeats that facilitate binding to ligands like Apolipoprotein B and E for cholesterol transport (Finkelshtein et al., 2013, PNAS). Crucially, the LDLR family has been identified as the primary entry port for Vesicular Stomatitis Virus (VSV) and its glycoprotein (VSV-G), which is widely used to pseudotype lentiviral vectors for gene therapy (Nikolic et al., 2018, Curr Opin Virol). The broad expression of LDLR family members across diverse tissues accounts for the wide tropism of VSV-G pseudotyped particles, making them highly efficient for transducing many cell types. In clinical practice, these receptors are targeted by lipid-lowering therapies such as statins and PCSK9 inhibitors (e.g., Alirocumab) to manage cardiovascular disease risk. Their role as viral entry receptors makes them central to the manufacturing of CAR-T cell therapies and other ex vivo gene-modified products. Beyond lipid transport and viral entry, members of this family are involved in signal transduction pathways critical for brain development and synaptic plasticity. Dysregulation of LDLR family members is associated with diseases ranging from familial hypercholesterolemia to Alzheimer's disease.

Other names

LDL receptor familyLDLR familyVesicular stomatitis virus receptorsLow-density lipoprotein receptor-related proteinsVSV-G receptorsLDL receptor family – viral entry receptors for VSV-G pseudotyped VLPs

The LDLR family facilitates cellular entry through clathrin-mediated endocytosis. For VSV-G pseudotyped particles, the VSV-G protein binds to the cysteine-rich repeats (CRs) in the ligand-binding domain of the receptor (Finkelshtein et al., 2013, PNAS). Following binding, the virus-receptor complex is internalized into endosomes, where the acidic environment triggers a conformational change in VSV-G, leading to membrane fusion and release of the viral genome or transgene into the cytosol (Nikolic et al., 2018, Curr Opin Virol). In cholesterol metabolism, the receptors bind ApoB-100 or ApoE on lipoproteins, internalize them, and then recycle back to the cell surface while the ligands are degraded in lysosomes.