Crystal structure of a copper-transporting PIB-type ATPase

Area of Science:

• Biochemistry
• Structural Biology
• Microbiology

Background:

• Heavy-metal homeostasis is vital for cellular survival and function.
• P-type ATPases of class IB (PIB) are critical for extruding toxic heavy metals from cells.

Purpose of the Study:

• To determine the structure of a PIB-ATPase, specifically Legionella pneumophila CopA Cu(+)-ATPase, in a copper-free state.
• To elucidate the copper transport pathway and mechanism of PIB-ATPases.
• To provide a structural basis for understanding human diseases linked to ATP7A and ATP7B.

Main Methods:

• X-ray crystallography at 3.2 Å resolution.
• Structural analysis of Legionella pneumophila CopA Cu(+)-ATPase.

Main Results:

• The copper-free structure of L. pneumophila CopA was determined.
• A three-stage copper transport pathway involving conserved residues was identified.
• A PIB-specific transmembrane helix with a double-glycine motif forms a putative intracellular copper entry point.
• A mechanism for ATPase-coupled copper release via an extracellular exit site was proposed.

Conclusions:

• The determined structure provides insights into heavy-metal extrusion mechanisms.
• The findings offer a framework for analyzing mutations in human ATP7A and ATP7B, implicated in Menkes' and Wilson's diseases.
• This research advances understanding of metalloenzyme structure and function in detoxification pathways.