Cholesteryl ester transfer between lipoproteins does not require a ternary tunnel complex with CETP

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• 作者：Matthias E. Lauer^a ; ¹ ; Alexandra Graff-Meyer^b ; ¹ ; Arne C. Rufer^a ; Cyrille Maugeais^a ; Elisabeth von der Mark^a ; Hugues Matile^a ; Brigitte D&rsquo ; Arcy^a ; Christine Magg^a ; ^c ; Philippe Ringler^b ; Shirley A. Mü ; ller^b ; Sebastian Scherer^b ; Gregor Dernick^a ; Ralf Thoma^a ; Michael Hennig^a ; ^d ; Eric J. Niesor^a ; ^{Eric.Niesor@bluewin.ch" class="auth_mail" title="E-mail the corresponding author} ; Henning Stahlberg^b ; ^{Henning.Stahlberg@unibas.ch" class="auth_mail" title="E-mail the corresponding author}
• 关键词：AUC ; analytical ultracentrifugation ; apoA1 ; apolipoprotein A1 ; apoB ; apolipoprotein B ; CE ; cholesteryl ester ; CETP ; cholesteryl ester transfer protein ; CVD ; cardiovascular disease ; Fab ; fragment antigen binding ; GST ; glutathione S-transferase ; HDL ; high-density lipoprotein ; LDL ; low-density lipoprotein ; mAb ; monoclonal antibody ; KD ; dissociation constant ; SEC ; size exclusion chromatography ; SPR ; surface plasmon resonance ; TEM ; transmission electron microscopy ; VLDL ; very low density lipoprotein
• 刊名：Journal of Structural Biology
• 出版年：2016
• 出版时间：May 2016
• 年：2016
• 卷：194
• 期：2
• 页码：191-198
• 全文大小：1911 K

文摘

The cholesteryl ester transfer protein (CETP) enables the transfer of cholesteryl ester (CE) from high-density lipoproteins (HDL) to low-density lipoproteins (LDL) in the plasma compartment. CETP inhibition raises plasma levels of HDL cholesterol; a ternary tunnel complex with CETP bridging HDL and LDL was suggested as a mechanism. Here, we test whether the inhibition of CETP tunnel complex formation is a promising approach to suppress CE transfer from HDL to LDL, for potential treatment of cardio-vascular disease (CVD). Three monoclonal antibodies against different epitopes of CETP are assayed for their potential to interfere with CE transfer between HDL and/or LDL. Surprisingly, antibodies that target the tips of the elongated CETP molecule, interaction sites sterically required to form the suggested transfer complexes, do not interfere with CETP activity, but an antibody binding to the central region does. We show that CETP interacts with HDL, but not with LDL. Our findings demonstrate that a ternary tunnel complex is not the mechanistic prerequisite to transfer CE among lipoproteins.