Versatility in ligand recognition by LDL receptor family proteins: advances and frontiers

Abstract

SummaryProteins of the low-density lipoprotein receptor family transport cholesterol-carrying particles into cells, clear protease-inhibitor complexes from the circulation, participate in biological signaling cascades, and even serve as viral receptors. These receptors utilize clusters of cysteine-rich LDL receptor type-A (LA) modules to bind many of their ligands. Recent structures show that these modules typically exhibit a characteristic binding mode to recognize their partners, relying primarily on electrostatic complementarity and avidity effects. The dominant contribution of electrostatic interactions with small interface areas in these complexes allows binding to be regulated by changes in pH via at least two distinct mechanisms. The structure of the subtilisin/kexin family protease PCSK9, a newly identified molecular partner of the LDLR also implicated in LDL-cholesterol homeostasis, also raises the possibility that the LDLR and its related family members may employ other strategies for pH-sensitive binding that have yet to be uncovered.

Site-specific O-glycosylation of members of the low-density lipoprotein receptor superfamily enhances ligand interactions

“…They are found as clusters of seven repeats in LDLR, eight in VLDLR and multiple clusters in LRP1 and LRP2, and they constitute the dominant ligand-binding region of these receptors ( Fig. 1) (5). The functional structure of the LA module requires a calcium ion coordinated by conserved acidic residues found between Cys4 and Cys6 in the LA sequence, and binding to different ligands appears to require different subsets of LA modules (6-9).…”

The PCSK9 decade

“…Measuring PCSK9 levels is, however, not an ideal surrogate marker for PCSK9 function, as most antibodies an extended (or open) conformation. The failure of the receptor to adopt a closed conformation in the endosome precludes normal recycling to the plasma membrane and targets the LDLR for lysosomal degradation ( 31,38 ) ( Fig. 1 ).…”

Up-regulation of ATP Binding Cassette Transporter A1 Expression by Very Low Density Lipoprotein Receptor and Apolipoprotein E Receptor 2

“…It is known that apoE is able to bind several members of the low density lipoprotein receptor (LDLR) family, including LDLR, very low density lipoprotein receptor (VLDLR), LDLRrelated protein-1 (LRP1), LRP2, and apoE receptor 2 (apoER2) (7). Although the role of the LDLR is limited to the regulation of cholesterol homeostasis by receptor-mediated endocytosis of lipoprotein particles, other members of this gene family have additional physiological functions (7).…”

“…Although the role of the LDLR is limited to the regulation of cholesterol homeostasis by receptor-mediated endocytosis of lipoprotein particles, other members of this gene family have additional physiological functions (7). For example, activation of VLDLR or apoER2 has been shown to activate disabled-1 (Dab1) and PI3K (8).…”