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Cupric Ions Selectively Modulate TRAAK–Phosphatidylserine Interactions

  • Yun Zhu
    Yun Zhu
    Department of Chemistry, Texas A&M University, College Station, Texas 77843, United States
    More by Yun Zhu
  • Samantha Schrecke
    Samantha Schrecke
    Department of Chemistry, Texas A&M University, College Station, Texas 77843, United States
  • Shuli Tang
    Shuli Tang
    Department of Chemistry, Texas A&M University, College Station, Texas 77843, United States
    More by Shuli Tang
  • Melanie T. Odenkirk
    Melanie T. Odenkirk
    Department of Chemistry, North Carolina State University, Raleigh, North Carolina 27695, United States
  • Thomas Walker
    Thomas Walker
    Department of Chemistry, Texas A&M University, College Station, Texas 77843, United States
  • Lauren Stover
    Lauren Stover
    Department of Chemistry, Texas A&M University, College Station, Texas 77843, United States
  • Jixing Lyu
    Jixing Lyu
    Department of Chemistry, Texas A&M University, College Station, Texas 77843, United States
    More by Jixing Lyu
  • Tianqi Zhang
    Tianqi Zhang
    Department of Chemistry, Texas A&M University, College Station, Texas 77843, United States
    More by Tianqi Zhang
  • David Russell
    David Russell
    Department of Chemistry, Texas A&M University, College Station, Texas 77843, United States
  • Erin S. Baker
    Erin S. Baker
    Department of Chemistry, North Carolina State University, Raleigh, North Carolina 27695, United States
    Comparative Medicine Institute, North Carolina State University, Raleigh, North Carolina 27695, United States
  • Xin Yan
    Xin Yan
    Department of Chemistry, Texas A&M University, College Station, Texas 77843, United States
    More by Xin Yan
  • , and 
  • Arthur Laganowsky*
    Arthur Laganowsky
    Department of Chemistry, Texas A&M University, College Station, Texas 77843, United States
    *Email: [email protected]
Cite this: J. Am. Chem. Soc. 2022, 144, 16, 7048–7053
Publication Date (Web):April 14, 2022
https://doi.org/10.1021/jacs.2c00612
Copyright © 2022 American Chemical Society

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    Abstract

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    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 (Ca2+, Mg2+, and Zn2+) bind both channels but have no impact on binding PS and other lipids. Additionally, TRAAK binds more avidly to Cu2+ and Zn2+ than TREK2. In the presence of Cu2+, TRAAK binds similarly to PS with different acyl chains, indicating a crucial role of the serine headgroup in coordinating Cu2+. 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. Interestingly, the next three highest coupling factors had a ∼1.5:1 PS-to-Cu2+ ratio. Our findings bring forth the role of cupric ions as an essential cofactor in selective TRAAK–PS interactions.

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