Low-density lipoprotein receptor adapter protein 1 (LDLRAP1)

Low-density lipoprotein receptor adapter protein 1 (LDLRAP1), also known as ARH, is a cytosolic adaptor protein required for the efficient internalization of the low-density lipoprotein receptor (LDLR) in hepatocytes (UniProt Q5SW96). It functions by specifically binding to the Asn-Pro-X-Tyr (NPXY) motif located within the cytoplasmic tail of the LDLR through its phosphotyrosine-binding (PTB) domain (Garcia et al., 2001, Science). Once bound, LDLRAP1 acts as a molecular bridge, interacting with clathrin and the adaptor protein complex 2 (AP-2) to facilitate the clustering of LDLR into clathrin-coated pits for endocytosis (He et al., 2002, J Biol Chem). This process is essential for the clearance of LDL cholesterol from the plasma. Defects in LDLRAP1 result in autosomal recessive hypercholesterolemia (ARH), a rare genetic disorder characterized by significantly elevated LDL cholesterol levels and premature coronary artery disease (Soutar and Naoumova, 2007, Hum Mol Genet). While there are currently no therapeutic agents that directly target LDLRAP1, it is a critical component of the pathway modulated by PCSK9 inhibitors and statins.

Other names

ARHAutosomal recessive hypercholesterolemia proteinLDLRAP1NPXY-binding proteinLDLR adaptor protein 1

LDLRAP1 binds the NPXY motif of the LDLR cytoplasmic tail via its PTB domain and recruits clathrin and AP-2 to initiate endocytosis.