Special Biochemistry Seminar

Lipids and metal ions, such as Cu2+ and Zn2+, are increasingly recognized for their ability to influence the structure and function of membrane proteins, including TRAAK and other two-pore domain K+ channels. However, the role of metal ions in the association of lipids with integral membrane proteins is poorly understood. Here, we discover Cu2+ can selectively modulate the binding of phosphatidylserine (PS) to TRAAK but not TREK2. Other divalent cations (Ca2+, Mg2+, and Zn2+) bind both channels but have no impact on binding PS and other lipids. High-resolution native mass spectrometry (MS) enables the determination of equilibrium binding constants for distinct Cu2+-bound stoichiometries and uncovered the highest coupling factor corresponds to a 1:1 PS-to-Cu2+ ratio. Our most recent work is uncovering the role Cu2+ and PS binding in modulating the structure and function of TRAAK. Collectively, our work is revealing a novel mechanism by which metal ions can exquisitely tune membrane protein function.