Cryo-electron microscopy structure of human ABCB6 transporter
Chunyu Wang1,2, Can Cao1,2, Nan Wang1,2
1National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
Protein Science : a Publication of the Protein Society
|October 2, 2020
Summary
The study reveals the molecular structure of human ATP-binding cassette transporter 6 (ABCB6), detailing its role in transporting toxic metals and drugs. Its unique structure supports ATPase activity and suggests a novel mechanism for substrate translocation involving glutathione.
Area of Science:
- Structural Biology
- Biochemistry
- Molecular Transport
Background:
- Human ATP-binding cassette transporter 6 (ABCB6) is an ABC transporter implicated in the movement of toxic metals and anticancer drugs.
- Understanding the molecular architecture of ABCB6 is crucial for elucidating its transport mechanisms and potential therapeutic applications.
Purpose of the Study:
- To determine the molecular structure of full-length human ABCB6 in an apo state using cryo-electron microscopy.
- To investigate the structural basis for ABCB6's ATPase activity and substrate binding.
- To explore the role of glutathione (GSH) in ABCB6-mediated substrate translocation.
Main Methods:
- Cryo-electron microscopy was employed to resolve the full-length ABCB6 structure.
- In vitro assays were conducted to assess ATPase activity.
- Porphyrin substrates and glutathione were used to study substrate translocation mechanisms.
Main Results:
- The cryo-EM structure revealed the architecture of full-length ABCB6, including two N-terminal transmembrane domains essential for ATPase activity.
- A slit-like substrate binding pocket suggests accommodation of planar porphyrins, with a secondary cavity facilitating substrate release.
- ABCB6's ATPase activity exhibited distinct profiles with various porphyrin substrates in the presence of GSH, indicating a GSH-dependent translocation mechanism.
Conclusions:
- The determined structure provides unprecedented insight into the architecture of full-length ABCB transporters.
- ABCB6 possesses structural features supporting its role in substrate translocation and ATPase activity.
- The findings suggest a novel, potentially GSH-cofactored, mechanism for ABCB6-mediated substrate transport.
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