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The structural basis for regulation of the glutathione transporter Ycf1 by regulatory domain phosphorylation

Author

Listed:
  • Nitesh Kumar Khandelwal

    (University of Arizona)

  • Cinthia R. Millan

    (University of Arizona)

  • Samantha I. Zangari

    (University of Arizona)

  • Samantha Avila

    (University of California – San Francisco
    Duke University School of Medicine)

  • Dewight Williams

    (Arizona State University)

  • Tarjani M. Thaker

    (University of Arizona)

  • Thomas M. Tomasiak

    (University of Arizona)

Abstract

Yeast Cadmium Factor 1 (Ycf1) sequesters heavy metals and glutathione into the vacuole to counter cell stress. Ycf1 belongs to the ATP binding cassette C-subfamily (ABCC) of transporters, many of which are regulated by phosphorylation on intrinsically-disordered domains. The regulatory mechanism of phosphorylation is still poorly understood. Here, we report two cryo-EM structures of Ycf1 at 3.4 Å and 4.0 Å resolution in inward-facing open conformations that capture previously unobserved ordered states of the intrinsically disordered regulatory domain (R-domain). R-domain phosphorylation is clearly evident and induces a topology promoting electrostatic and hydrophobic interactions with Nucleotide Binding Domain 1 (NBD1) and the Lasso motif. These interactions stay constant between the structures and are related by rigid body movements of the NBD1/R-domain complex. Biochemical data further show R-domain phosphorylation reorganizes the Ycf1 architecture and is required for maximal ATPase activity. Together, we provide insights into how R-domains control ABCC transporter activity.

Suggested Citation

  • Nitesh Kumar Khandelwal & Cinthia R. Millan & Samantha I. Zangari & Samantha Avila & Dewight Williams & Tarjani M. Thaker & Thomas M. Tomasiak, 2022. "The structural basis for regulation of the glutathione transporter Ycf1 by regulatory domain phosphorylation," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28811-w
    DOI: 10.1038/s41467-022-28811-w
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    1. Yao-Xu Mao & Zhi-Peng Chen & Liang Wang & Jie Wang & Cong-Zhao Zhou & Wen-Tao Hou & Yuxing Chen, 2024. "Transport mechanism of human bilirubin transporter ABCC2 tuned by the inter-module regulatory domain," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    2. Nitesh Kumar Khandelwal & Thomas M. Tomasiak, 2024. "Structural basis for autoinhibition by the dephosphorylated regulatory domain of Ycf1," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    3. Yongxiang Zhao & Heidi Schubert & Alan Blakely & Biff Forbush & Micholas Dean Smith & Jesse Rinehart & Erhu Cao, 2024. "Structural bases for Na+-Cl− cotransporter inhibition by thiazide diuretic drugs and activation by kinases," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    4. Tiziano Mazza & Theodoros I. Roumeliotis & Elena Garitta & David Drew & S. Tamir Rashid & Cesare Indiveri & Jyoti S. Choudhary & Kenneth J. Linton & Konstantinos Beis, 2024. "Structural basis for the modulation of MRP2 activity by phosphorylation and drugs," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    5. Dian Ding & Tianyi Hou & Miao Wei & Jing-Xiang Wu & Lei Chen, 2023. "The inhibition mechanism of the SUR2A-containing KATP channel by a regulatory helix," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

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