Century of Progress on the Structure of APOB-100 in Atherogenic Lipoproteins

APOB-100 (apolipoprotein B100) is the obligate structural protein of very low-density lipoprotein (VLDL), intermediate density lipoprotein, and low-density lipoprotein (LDL), with each atherogenic particle containing a single copy. Because circulating APOB concentration reflects particle number, it has emerged as a clinically important marker that may outperform LDL cholesterol in cardiovascular risk prediction. Historically, the large size, lipid dependence, and conformational diversity of APOB have hindered a detailed structural understanding. However, recent advances in cryo-electron microscopy and integrative modeling have transformed this landscape, yielding near-atomic models of APOB organization on human LDL and defining the structural basis for receptor recognition. This review traces the evolution of APOB structural concepts from its discovery as the main LDL scaffold to contemporary cryo-electron microscopy-derived architectures. The new structures reveal an extended scaffold that encircles the particle, accommodates large changes in lipid cargo, and presents multiple interaction surfaces for the LDL receptor. The new models reconcile decades of mutagenesis, antibody mapping, and cross-linking data and provide a mechanistic framework for understanding familial hypercholesterolemia variants, receptor binding stoichiometry, and the structural transitions that occur during VLDL to LDL remodeling. Despite these advances, intrinsic heterogeneity in particle size, lipid composition, and protein conformation imposes fundamental limits on achievable resolution, and we argue that APOB should be viewed as a dynamic structural ensemble rather than a single static molecule. Future work will require integration of structural models with targeted biochemical studies to define cooperative receptor binding mechanisms, structural determinants of remnant clearance, and the basis for association with exchangeable apolipoproteins and lipolysis regulators. Extending cryo electron microscopy to LDL subpopulations like lipoprotein(a) and VLDL remnants promises to establish new frameworks for linking APOB architecture to lipoprotein metabolism and cardiovascular disease.