Article Impact Level: HIGH Data Quality: STRONG Summary of Nature. https://doi.org/10.1038/s41586-024-08467-w Dr. Zachary T. Berndsen et al.
Points
- Researchers used cryo-electron microscopy (cryo-EM) and AI to map the structure of apolipoprotein B100 (apoB100), a key component of low-density lipoprotein (LDL).
- ApoB100 consists of a globular N-terminal domain and a 61 nm-long amphipathic β-sheet, stabilized by nine interstrand inserts that maintain LDL particle integrity.
- Molecular dynamics refinement and AlphaFold neural networks enhanced the structural resolution, uncovering apoB100’s interactions with the lipid membrane.
- Understanding apoB100’s structure may lead to targeted cholesterol-lowering treatments that reduce atherosclerosis risk while minimizing the side effects of existing therapies.
- The study underscores the role of cryo-EM and AI in molecular research, paving the way for improved cardiovascular treatments and diagnostic tools.
Summary
In a recent study, researchers employed cryo-electron microscopy (cryo-EM) combined with artificial intelligence to reveal the intricate structure of apolipoprotein B100 (apoB100), a key protein component of low-density lipoprotein (LDL). The study, conducted by University of Missouri experts, utilized advanced cryo-EM technology to resolve apoB100’s structure to subnanometer precision. ApoB100 forms the structural backbone of LDL, enabling its transport through the bloodstream, and its role in atherosclerosis and heart disease has been well-established. The research uncovered that apoB100 consists of a large globular N-terminal domain and a continuous 61 nm-long amphipathic β-sheet that wraps around the LDL particle. The β-belt is supported by nine interstrand inserts that provide structural cohesion and maintain the LDL shape across varying particle sizes.
The study incorporated a combination of molecular dynamics-based refinement and AlphaFold neural networks to enhance the resolution and accuracy of the apoB100 structure. This approach helped uncover the protein’s detailed interaction with the surrounding lipid membrane and its role in stabilizing LDL. The findings demonstrate how the apoB100 domains work together to ensure LDL integrity and functionality. A comprehensive list of over 200 intramolecular cross-links showed close agreement with the proposed structure, further validating the model. This structural understanding could lead to targeted treatments for high cholesterol and atherosclerosis, potentially improving patient outcomes while minimizing side effects associated with current cholesterol-lowering therapies, such as statins.
The structural insights into apoB100 could have profound implications for future drug development. Understanding the exact role apoB100 in lipid metabolism provides a foundation for creating more precise therapies targeting LDL particles, aiming to reduce heart disease risks without affecting cholesterol’s other beneficial roles in the body. The study highlights the critical intersection of cryo-EM and AI in advancing molecular-level understanding and presents a pathway toward better diagnostic tools and treatments for cardiovascular disease.
Link to the article: https://www.nature.com/articles/s41586-024-08467-w
References Berndsen, Z. T., & Cassidy, C. K. (2024). The structure of apolipoprotein B100 from human low-density lipoprotein. Nature. https://doi.org/10.1038/s41586-024-08467-w
