TABLE 1.

Data supporting the tunnel hypothesis for CETP-mediated lipid exchange (2)

1. EM studies show HDL visually connected or bridged to LDL or VLDL by CETP (Fig. 1C).

2. CETP's ends penetrate the lipoproteins, forming a ternary complex (Fig. 1C).

3. X-ray crystallographic analyses show unconnected hydrophobic cavities located in the central axis of both the N- and C-terminal domains and lateral to the 60 Å long central cavity.

4. Molecular dynamics simulation data suggest that only minor twisting (15°) along the long axis of CETP creates 10° of tilt  within the β-barrel strands.

5. Torsional analysis suggests that 10° of tilting causes these cavities to become connected to each other and to the central cavity, forming a long, continuous, hydrophobic tunnel that extends the full length of CETP.

6. The tunnel has appropriate space and hydrophobicity capable of accommodating neutral lipids, e.g., CE and triglyceride.

7. Functional EM studies indicate that after CETP ternary complex formation between HDL and LDL, HDL particles decrease in size in the ternary complex, presumably due to CE transfer to LDL (Fig. 1D).

8. EM HDL size analyses of the ternary complexes permit an approximate CE transfer rate constant of 0.58 ± 0.19/ h (r > 0.94) to be calculated.

9. CETP C-terminal domain-specific antibody, which inhibits CETP's association with LDL, inhibits functional CE transfer.

10. CETP is deeply embedded into HDL and apparently has no off-rate after binding to HDL after several hours.