TY - JOUR
T1 - Cholesterol efflux mechanism revealed by structural analysis of human ABCA1 conformational states
AU - Sun, Yingyuan
AU - Li, Xiaochun
N1 - Funding Information:
Cryo-EM data were collected at the UT Southwestern Medical Center Cryo-EM Facility (funded in part by the CPRIT Core Facility Support Award RP170644). We thank our colleagues D. Stoddard and J. Diaz for assistance in data collection, E. Debler and P. Schmiege for editing during manuscript preparation and Y. Liu for advising on the cholesterol efflux assay. This work was supported by National Institutes of Health grants P01HL020948, R01HL072304 and R01GM135343 (to X.L.). X.L. is a Damon Runyon-Rachleff Innovator supported by the Damon Runyon Cancer Research Foundation (DRR-53S-19) and a Rita C. and William P. Clements Jr. Scholar in Biomedical Research at UT Southwestern Medical Center.
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022/3
Y1 - 2022/3
N2 - ATP-binding cassette transporter A1 (ABCA1) utilizes energy derived from ATP hydrolysis to export cholesterol and phospholipids from macrophages. ABCA1 plays a central role in the biosynthesis of high-density lipoprotein (HDL), which mediates reverse cholesterol transport and prevents detrimental lipid deposition. Mutations in ABCA1 cause Tangier disease characterized by a remarkable reduction in the amount of HDL in blood. Here we present cryo-electron microscopy structures of human ABCA1 in ATP-bound and nucleotide-free states. Structural comparison reveals that ATP molecules pull the nucleotide-binding domains together, inducing movements of transmembrane helices 1, 2, 7 and 8 through a series of salt-bridge interactions. Subsequently, extracellular domains (ECDs) undergo a rotation and introduce conformational changes in the ECD–transmembrane interface. In addition, while we observe a sterol-like molecule in ECDs, no such density was observed in the structure of an HDL-deficiency mutant ABCA1Y482C, demonstrating the physiological importance of ECDs and a putative interaction mode between ABCA1 and its lipid acceptors. Thus, these structures, along with cholesterol efflux assays, advance the understanding ABCA1-mediated reverse cholesterol transport.
AB - ATP-binding cassette transporter A1 (ABCA1) utilizes energy derived from ATP hydrolysis to export cholesterol and phospholipids from macrophages. ABCA1 plays a central role in the biosynthesis of high-density lipoprotein (HDL), which mediates reverse cholesterol transport and prevents detrimental lipid deposition. Mutations in ABCA1 cause Tangier disease characterized by a remarkable reduction in the amount of HDL in blood. Here we present cryo-electron microscopy structures of human ABCA1 in ATP-bound and nucleotide-free states. Structural comparison reveals that ATP molecules pull the nucleotide-binding domains together, inducing movements of transmembrane helices 1, 2, 7 and 8 through a series of salt-bridge interactions. Subsequently, extracellular domains (ECDs) undergo a rotation and introduce conformational changes in the ECD–transmembrane interface. In addition, while we observe a sterol-like molecule in ECDs, no such density was observed in the structure of an HDL-deficiency mutant ABCA1Y482C, demonstrating the physiological importance of ECDs and a putative interaction mode between ABCA1 and its lipid acceptors. Thus, these structures, along with cholesterol efflux assays, advance the understanding ABCA1-mediated reverse cholesterol transport.
UR - http://www.scopus.com/inward/record.url?scp=85136941499&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85136941499&partnerID=8YFLogxK
U2 - 10.1038/s44161-022-00022-y
DO - 10.1038/s44161-022-00022-y
M3 - Article
C2 - 37181814
AN - SCOPUS:85136941499
SN - 2731-0590
VL - 1
SP - 238
EP - 245
JO - Nature Cardiovascular Research
JF - Nature Cardiovascular Research
IS - 3
ER -