Open AccessCupric Ions Selectively Modulate TRAAK–Phosphatidylserine Interactions
Author(s) -
Yun Zhu,
Samantha Schrecke,
Shuli Tang,
Melanie T. Odenkirk,
Thomas E. Walker,
Lauren Stover,
Jixing Lyu,
Tianqi Zhang,
David H. Russell,
Erin Baker,
Xingru Yan,
Arthur Laganowsky
Publication year - 2022
Publication title -
journal of the american chemical society
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.115
H-Index - 612
eISSN - 1520-5126
pISSN - 0002-7863
DOI - 10.1021/jacs.2c00612
Subject(s) - chemistry , phosphatidylserine , phosphatidic acid , divalent , protein–lipid interaction , ion , serine , cofactor , membrane , biophysics , membrane protein , phospholipid , biochemistry , integral membrane protein , enzyme , organic chemistry , biology
TRAAK and TREK2 are two-pore domain K + (K2P) channels and are modulated by diverse factors including temperature, membrane stretching, and lipids, such as phosphatidic acid. In addition, copper and zinc, both of which are essential for life, are known to regulate TREK2 and a number of other ion channels. However, the role of ions in the association of lipids with integral membrane proteins is poorly understood. Here, we discover cupric ions selectively modulate the binding of phosphatidylserine (PS) to TRAAK but not TREK2. Other divalent cations (Ca 2+ , Mg 2+ , and Zn 2+ ) bind both channels but have no impact on binding PS and other lipids. Additionally, TRAAK binds more avidly to Cu 2+ and Zn 2+ than TREK2. In the presence of Cu 2+ , TRAAK binds similarly to PS with different acyl chains, indicating a crucial role of the serine headgroup in coordinating Cu 2+ . High-resolution native mass spectrometry (MS) enables the determination of equilibrium binding constants for distinct Cu 2+ -bound stoichiometries and uncovered the highest coupling factor corresponds to a 1:1 PS-to-Cu 2+ ratio. Interestingly, the next three highest coupling factors had a ∼1.5:1 PS-to-Cu 2+ ratio. Our findings bring forth the role of cupric ions as an essential cofactor in selective TRAAK-PS interactions.