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Structure of the Human Cholesterol Transporter ABCG1.
Liga Skarda1, Julia Kowal1, Kaspar P Locher1
1Institute of Molecular Biology and Biophysics, ETH Zurich, Otto-Stern-Weg 5, 8093 Zürich, Switzerland.
Journal of Molecular Biology
|August 30, 2021
Summary
This study reveals the cryo-EM structure of the cholesterol transporter ABCG1, proposing a mechanism for its function in removing excess cholesterol and preventing cardiovascular disease.
Area of Science:
- Biochemistry
- Structural Biology
- Molecular Mechanisms
Background:
- ATP binding cassette (ABC) transporters play crucial roles in cellular lipid homeostasis.
- ABCG1 facilitates cholesterol efflux from peripheral tissues, crucial for preventing cardiovascular and metabolic diseases.
- The precise mechanism of ABCG1-mediated cholesterol transport remains poorly understood.
Purpose of the Study:
- To elucidate the structural basis of ABCG1 function.
- To determine the mechanism of cholesterol transport mediated by ABCG1.
- To compare ABCG1 structure and function with related ABC transporters.
Main Methods:
- Cryo-electron microscopy (cryo-EM) to determine the structure of human ABCG1.
- Biochemical assays to assess ATPase activity using liposome-reconstituted ABCG1.
- Inhibitor studies using benzamil, taurocholate, and Ko143.
Main Results:
- A 4 Å resolution cryo-EM structure of human ABCG1 in an inward-open state was obtained.
- Sterol-like density was observed within the ABCG1 binding cavity.
- Structural comparisons highlighted mechanistic differences and substrate specificity between ABCG1, ABCG2, and ABCG5/G8.
- Benzamil and taurocholate inhibited ABCG1 ATPase activity, while Ko143 did not.
Conclusions:
- The determined structure provides key insights into the mechanism of ABCG1-mediated cholesterol transport.
- Understanding ABCG1's mechanism is vital for developing strategies against lipid accumulation and related diseases.
- Structural and functional comparisons reveal distinct roles and specificities among ABC transporters involved in lipid transport.
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