Low-density lipoprotein receptor class A domain (LDLR-A domain) (LDLR-A domain)

The Low-density lipoprotein receptor (LDLR) class A domain, also known as a cysteine-rich repeat or LA repeat, is a structural motif of approximately 40 amino acids characterized by six conserved cysteine residues and a calcium-binding cluster (InterPro: IPR002172). These domains function as the primary ligand-binding modules within the LDL receptor family, facilitating the recognition and endocytosis of cholesterol-carrying lipoproteins like LDL and VLDL (UniProt: P01130). In humans, the LDLR contains seven of these repeats, which are essential for maintaining cholesterol homeostasis by clearing apolipoprotein B- and E-containing particles from the blood (PubMed: 12456330). Mutations within these cysteine-rich domains are a frequent cause of Familial Hypercholesterolemia, leading to severely elevated plasma LDL levels and premature cardiovascular disease (StatPearls: NBK448182). Beyond lipid metabolism, these domains are found in various other proteins where they mediate protein-protein interactions involved in signal transduction and protease inhibition (PubMed: 10651644). While most current therapies like PCSK9 inhibitors (e.g., Evolocumab) do not bind these domains directly, they work by preventing the lysosomal degradation of the receptors that contain them, thereby increasing the availability of these binding sites on the hepatocyte surface (PubMed: 24578244).

Other names

LDL receptor type A repeatLA repeatComplement-type repeatCysteine-rich repeatLDLR class A domain

Inhibition of PCSK9 to prevent the degradation of receptors containing these domains, thereby increasing their density on the cell surface to facilitate LDL clearance.