Article Impact Level: HIGH Data Quality: STRONG Summary of Nature, 1–7. https://doi.org/10.1038/s41586-024-08223-0 Dr. Mart Reimund et al.
Points
- The study used cryo-electron microscopy to reveal how LDL (“bad cholesterol”) binds to its receptor (LDLR), a critical process for cholesterol clearance from the bloodstream.
- High-resolution imaging identified two distinct binding interfaces between apoB100, the structural protein of LDL, and LDLR, crucial for understanding LDL accumulation in cardiovascular disease.
- Mutations in apoB100 and LDLR that impair their interaction were mapped to the binding interface, shedding light on the genetic basis of FH and its associated elevated LDL levels.
- The findings highlight potential strategies for personalized treatments targeting the LDL–LDLR binding interface, improving therapies for FH, and enhancing LDL-lowering drugs like statins.
- The study paves the way for developing targeted therapies to improve LDL clearance, which would benefit genetic mutation carriers and individuals with high cholesterol.
Summary
A recent study utilizing cryo-electron microscopy has provided a detailed structural understanding of how low-density lipoprotein (LDL), commonly known as “bad” cholesterol, binds to its receptor (LDLR), a crucial step in the clearance of LDL from the bloodstream. The research, published in Nature, reveals the structural components of apolipoprotein B100 (apoB100), the main structural protein of LDL, and how it interacts with LDLR to initiate this clearance. The researchers used advanced imaging techniques to visualize the LDL–LDLR complex at high resolution, allowing them to identify two distinct binding interfaces between the two proteins. These insights are pivotal in understanding the mechanisms behind LDL accumulation in cardiovascular disease, particularly in cases of familial hypercholesterolemia (FH), a genetic disorder that causes elevated LDL levels.
The study also identified specific mutations in apoB100 and LDLR that impair their interaction, leading to the buildup of LDL in the blood, a hallmark of FH. These mutations were mapped to the LDL–LDLR binding interface, providing a new understanding of how these genetic defects contribute to the disease. The research demonstrated that FH-associated variants of apoB100 and LDLR are concentrated in these critical regions, suggesting that targeting these areas may be a potential therapeutic strategy. The findings have important implications for developing personalized treatments for individuals with FH and improving the efficacy of LDL-lowering drugs like statins.
In addition to advancing our knowledge of the molecular basis of LDL metabolism, the study’s insights could lead to the development of more targeted therapies for cholesterol management. By focusing on the specific binding mechanisms between LDL and LDLR, researchers now have the potential to design drugs that enhance LDL clearance, not only for patients with genetic mutations but also for those with high cholesterol who may benefit from improved statin treatments. These findings open new avenues for genetic and non-genetic approaches to treating cardiovascular disease linked to high cholesterol.
Link to the article: https://www.nature.com/articles/s41586-024-08223-0
References Reimund, M., Dearborn, A. D., Graziano, G., Lei, H., Ciancone, A. M., Kumar, A., Holewinski, R., Neufeld, E. B., O’Reilly, F. J., Remaley, A. T., & Marcotrigiano, J. (2024). Structure of apolipoprotein B100 bound to the low-density lipoprotein receptor. Nature, 1–7. https://doi.org/10.1038/s41586-024-08223-0
