Structural heterogeneity of apolipoprotein B-100

Area of Science:

• Structural Biology
• Cardiovascular Science
• Biochemistry

Background:

• Cardiovascular disease (CVD) poses a significant global health burden, impacting morbidity and mortality.
• Current drug strategies for CVD prevention often target the interaction between the low-density lipoprotein receptor (LDLR) and apolipoprotein B-100 (apoB-100) on low-density lipoprotein (LDL).
• Understanding the structural basis of this interaction is crucial for developing effective therapies.

Purpose of the Study:

• To determine the high-resolution structure of apoB-100 on LDL.
• To elucidate the structural basis of apoB-100 interaction with LDLR.
• To investigate structural heterogeneity and conformational flexibility of apoB-100.

Main Methods:

• Cryo-electron microscopy (cryo-EM) was employed to determine the structure of apoB-100 on LDL.
• Structural analysis was performed in both the absence and presence of LDLR.
• Computational modeling and visualization techniques were utilized to interpret structural features.

Main Results:

• The structure revealed that the C-terminal two-thirds of apoB-100 (>3000 residues) lack significant tertiary structure.
• ApoB-100 forms amphipathic helices and β-sheets on the LDL surface, enveloping the lipid core.
• The LDLR binding domain involves multiple sites on a circumferential β-belt and the N-terminus of apoB-100.
• Structural heterogeneity and multiple conformations of apoB-100 were observed.

Conclusions:

• The unique structural organization of apoB-100 facilitates its interaction with LDLR.
• Observed conformational flexibility may enable apoB-100 to bind different lipoprotein sizes and interact with other molecules.
• These findings provide critical structural insights into LDL metabolism and potential therapeutic targets for cardiovascular disease.