Targeting structural flexibility in low density lipoprotein by integrating cryo-electron microscopy and high-speed...

Area of Science:

• Biochemistry
• Structural Biology
• Biophysics

Background:

• Low-density lipoprotein (LDL) is central to cholesterol transport and its arterial accumulation drives cardiovascular diseases like atherosclerosis.
• Understanding LDL's molecular structure and apolipoprotein B-100 (apo B-100) dynamics is crucial for comprehending its role in disease.

Purpose of the Study:

• To elucidate the molecular structure and dynamics of LDL, focusing on apo B-100.
• To revise the model of LDL core organization and identify surface features.

Main Methods:

• Single-particle cryo-electron microscopy (cryo-EM) for high-resolution structural determination.
• High-speed atomic force microscopy (HS-AFM) for real-time molecular motion analysis.
• 3D variability analysis to address LDL flexibility and heterogeneity.

Main Results:

• A revised model for LDL core organization, particularly cholesterol ester (CE) arrangement.
• Identification of a high-density region near poles, likely containing free cholesterol.
• Discovery of two surface protrusions attributed to apo B-100, exhibiting large domain fluctuations in real-time.

Conclusions:

• The study provides unprecedented dynamic insights into LDL structure using HS-AFM.
• A detailed understanding of LDL's intrinsic flexibility, a complex interplay of lipids and protein, is achieved.
• This work refines models of LDL structure and dynamics, relevant to cardiovascular disease research.