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

Nitesh Kumar Khandelwal, Cinthia R. Millan, Samantha I. Zangari, Samantha Avila, Dewight Williams, Tarjani M. Thaker and Thomas M. Tomasiak ()
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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
Dewight Williams: Arizona State University
Tarjani M. Thaker: University of Arizona
Thomas M. Tomasiak: University of Arizona

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-28811-w

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