How cholesteryl ester transfer protein can also be a potential triglyceride transporter

Area of Science:

• Biochemistry
• Structural Biology
• Computational Biology

Background:

• Cholesteryl ester transfer protein (CETP) facilitates lipid transfer between lipoproteins, making it a drug target for cardiovascular disease (CVD).
• Existing research primarily focused on CE-bound CETP, leaving the TG-bound state under-explored despite its functional significance.

Purpose of the Study:

• To elucidate the structure and dynamics of triglyceride (TG)-bound CETP.
• To understand the molecular mechanisms underlying TG transfer by CETP.

Main Methods:

• Large-scale all-atom and coarse-grained Molecular Dynamics (MD) simulations.
• Structural analysis and comparison with existing functional and mutagenesis data.

Main Results:

• CETP accommodates two TG molecules in a parallel orientation, with TG oleate chains adopting a tuning-fork conformation.
• TG-bound CETP maintains secondary structures and exhibits similar motions to CE-bound CETP.
• TGs form 20% more contacts with CETP than CEs, consistent with slower TG transfer rates.

Conclusions:

• The study provides key structural insights into TG-bound CETP, crucial for understanding its function.
• Findings can accelerate the design of novel therapeutics targeting CETP for CVD treatment.