Cryo-EM structure of cadmium-bound human ABCB6

Area of Science:

• Biochemistry
• Structural Biology
• Cell Biology

Background:

• ATP-binding cassette transporter B6 (ABCB6) is crucial for heme biosynthesis and heavy metal detoxification.
• Understanding ABCB6's heavy metal binding mechanism is vital for cellular protection.

Purpose of the Study:

• To elucidate the structural basis of human ABCB6 binding to cadmium (Cd(II)) in the presence of glutathione (GSH) and phytochelatin 2 (PC2).
• To compare the binding modes and identify structural determinants of substrate specificity in ABCB6 and related transporters.

Main Methods:

• Cryo-electron microscopy (cryo-EM) was used to determine the structures of human ABCB6 bound to Cd(II) with GSH or PC2.
• High-resolution structural analysis (3.2 and 3.1 Å) revealed molecular interactions and conformational changes.

Main Results:

• Human ABCB6 adopts an inward-facing conformation with reduced separation between transporter halves when bound to Cd(II).
• Cd(II) is coordinated by two GSH molecules or two PC2 molecules, forming tetrathiolate complexes.
• Specific residues within the binding cavity and variations in capping residues influence substrate specificity.

Conclusions:

• The structures provide atomic-level insights into ABCB6-mediated cadmium transport and detoxification.
• Structural differences in homologous transporters, particularly capping residues, explain their distinct substrate specificities.