| Cubilin is a large multiligand endocytic receptor of the CUB‑domain–containing family that is expressed at the apical surface of absorptive epithelia in the small intestine, renal proximal tubule, visceral yolk sac, and placenta, where it partners with amnionless and megalin to mediate receptor‑driven uptake of carrier‑bound nutrients and filtered plasma proteins. The ectodomain is built from a series of EGF‑like modules followed by 27 CUB domains that form repeated Ca²⁺‑binding ligand‑interaction modules; the C‑terminal half of cubilin contains a large subset of these CUB domains and contributes substantially to ligand binding and receptor multivalency. Calcium‑coordinated CUB domains in this region bind the intrinsic factor–cobalamin complex, albumin, apolipoprotein A‑I, transferrin, hemoglobin, vitamin D–binding protein (GC), immunoglobulin light chains, and high‑density lipoprotein particles, and biochemical mapping indicates that discrete CUB‑domain clusters within the C‑terminal portion provide overlapping but distinct binding sites for IF–B12 and albumin, allowing simultaneous or competitive capture of these ligands at the brush border. Cubilin lacks a transmembrane segment and relies on its N‑terminal interaction with amnionless to form the cubam complex, which anchors the receptor in the membrane and couples ligand‑occupied cubilin to clathrin‑mediated endocytosis and downstream endosomal trafficking, while cooperation with megalin further expands ligand repertoires and endocytic capacity. The C‑terminal half of cubilin is critical for renal protein reabsorption, and human C‑terminal CUBN variants that alter surface expression or ligand binding associate with chronic isolated albuminuria in the presence of preserved glomerular filtration and normal renal function, with the region as a determinant of proximal tubular albumin uptake efficiency rather than glomerular barrier integrity. |
