[PNAS] ABCA1 dimer-monomer interconversion during HDL generation revealed by single-molecule imaging

• Publication Information

12 March 2013

The generation of high-density lipoprotein (HDL), one of the most critical events for preventing atherosclerosis, is mediated by ATP-binding cassette protein A1 (ABCA1). ABCA1 is known to transfer cellular cholesterol and phospholipids to apolipoprotein A-I (apoA-I) for generating discoidal HDL (dHDL) particles, composed of 100-200 lipid molecules surrounded by two apoA-I molecules; however, the regulatory mechanisms are still poorly understood. Here Koh O. Nagata, Akihiro Kusumi, and Kazumitsu Ueda at Kyoto University iCeMS and their colleagues observed ABCA1-GFP and apoA-I at the level of single molecules on the plasma membrane via a total internal reflection fluorescence microscope. The team found that about 70% of total ABCA1-GFP spots are immobilized on the plasma membrane and estimated that about 89% of immobile ABCA1 molecules are in dimers. Furthermore, an ATPase-deficient ABCA1 mutant failed to be immobilized or form a dimer. The team found that the lipid acceptor apoA-I interacts with the ABCA1 dimer to generate dHDL and is followed by ABCA1 dimer-monomer interconversion. This indicates that the formation of the ABCA1 dimer is the key for apoA-I binding and nascent HDL generation. Their findings suggest the physiological significance of conversion of the ABCA1 monomer to a dimer: The dimer serves as a receptor for two apoA-I molecules for dHDL particle generation. [Read more at the PNAS website]

These findings have received nationwide media coverage in Japan.

Publication Information

ABCA1 dimer-monomer interconversion during HDL generation revealed by single-molecule imaging

Koh O. Nagata^a, Chieko Nakada^a,1, Rinshi S. Kasai^b, Akihiro Kusumi^a,b,2, and Kazumitsu Ueda^a,c,2

Proceedings of the National Academy of Sciences of the United States of America (PNAS) | Published online 11 March 2013 | DOI: 10.1073/pnas.1220703110

• Institute for Integrated Cell-Material Sciences (WPI-iCeMS), and
• Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kyoto, 606-8502, Japan; and
• Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan

1. Present address: Bio Science Development Department, Instruments Company, Nikon Corp., Yokohama 244-8533, Japan.
2. To whom correspondence may be addressed.