LDLa

LDLa, short for the LDL receptor class A domain, is a small extracellular motif found in a wide range of proteins of the low-density lipoprotein receptor (LDLR) family. Also known as LA repeats, LDLa domains are modular elements that contribute to ligand binding and receptor endocytosis. They are typically arranged in tandem within the extracellular ligand-binding region of receptors such as LDLR, VLDLR, ApoER2, and several members of the LDL receptor-related protein (LRP) family, as well as some non-LDLR proteins.

Each LDLa domain is about 40 amino acids long and contains six highly conserved cysteine residues that form three disulfide bonds. A calcium-binding site is a defining feature of the domain, and calcium ions stabilize the domain’s conformation, enabling effective interaction with ligands. A characteristic motif with acidic residues, including sequences like DxxDxDxD, coordinates calcium in conjunction with surrounding residues. The presence and arrangement of multiple LDLa repeats influence binding affinity for apolipoprotein B/E-containing ligands and affect receptor-mediated endocytosis.

Functionally, LDLa domains mediate calcium-dependent ligand binding and help position ligands for internalization by endocytosis. They play a key role in lipid metabolism and cellular signaling through their participation in the activity of LDLR family receptors. Variants that alter the number, sequence, or integrity of LDLa repeats can impair receptor function, contributing to disruptions in ligand binding and uptake, with potential implications for lipid homeostasis and development.

In research, LDLa domains are studied to understand receptor–ligand interactions and have been used as modular calcium-binding domains in protein engineering and structural analyses.