Inositol pyrophosphates activate the vacuolar transport chaperone complex in yeast by disrupting a homotypic SPX domain interaction

Joka Pipercevic, Bastian Kohl, Ruta Gerasimaite, Véronique Comte-Miserez, Sarah Hostachy, Thomas Müntener, Elia Agustoni, Henning Jacob Jessen, Dorothea Fiedler, Andreas Mayer and Sebastian Hiller ()
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Joka Pipercevic: University of Basel
Bastian Kohl: University of Basel
Ruta Gerasimaite: University of Lausanne
Véronique Comte-Miserez: University of Lausanne
Sarah Hostachy: Leibniz-Forschungsinstitut für Molekulare Pharmakologie
Thomas Müntener: University of Basel
Elia Agustoni: University of Basel
Henning Jacob Jessen: University of Freiburg
Dorothea Fiedler: Leibniz-Forschungsinstitut für Molekulare Pharmakologie
Andreas Mayer: University of Lausanne
Sebastian Hiller: University of Basel

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract Many proteins involved in eukaryotic phosphate homeostasis are regulated by SPX domains. In yeast, the vacuolar transporter chaperone (VTC) complex contains two such domains, but mechanistic details of its regulation are not well understood. Here, we show at the atomic level how inositol pyrophosphates interact with SPX domains of subunits Vtc2 and Vtc3 to control the activity of the VTC complex. Vtc2 inhibits the catalytically active VTC subunit Vtc4 by homotypic SPX–SPX interactions via the conserved helix α1 and the previously undescribed helix α7. Binding of inositol pyrophosphates to Vtc2 abrogates this interaction, thus activating the VTC complex. Accordingly, VTC activation is also achieved by site-specific point mutations that disrupt the SPX–SPX interface. Structural data suggest that ligand binding induces reorientation of helix α1 and exposes the modifiable helix α7, which might facilitate its post-translational modification in vivo. The variable composition of these regions within the SPX domain family might contribute to the diversified SPX functions in eukaryotic phosphate homeostasis.

Date: 2023
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DOI: 10.1038/s41467-023-38315-w

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