Molecular insights into substrate translocation in an elevator-type metal transporter

Area of Science:

• Biochemistry
• Structural Biology
• Computational Biology

Background:

• Zrt/Irt-like protein (ZIP) transporters are crucial for essential microelement homeostasis.
• The transport mechanism and conformational changes of the prototypical Bordetella bronchiseptica ZIP (BbZIP) transporter remain unclear.

Purpose of the Study:

• To elucidate the metal substrate translocation pathway and conformational changes in BbZIP.
• To understand the mechanisms of metal release and cytoplasmic regulation of BbZIP activity.

Main Methods:

• Combined structural, biochemical, and computational approaches.
• High-resolution crystal structure analysis of a cross-linked BbZIP variant.
• Enhanced sampling simulations to study transporter dynamics.

Main Results:

• Revealed an upward hinge motion of the transport domain in the crystal structure.
• Elucidated metal release mechanisms into the cytoplasm.
• Identified a cytoplasmic metal-binding loop regulating transporter activity.
• Unraveled an unusual elevator transport mode distinct from other known elevator transporters.

Conclusions:

• BbZIP utilizes a unique elevator mechanism for metal transport.
• Structural and dynamic insights into ZIP family metal transport mechanisms.
• Provides a foundation for understanding microelement homeostasis regulation.