Doa10/MARCH6 architecture interconnects E3 ligase activity with lipid-binding transmembrane channel to regulate SQLE

J. Josephine Botsch, Roswitha Junker, Michèle Sorgenfrei, Patricia P. Ogger, Luca Stier, Susanne Gronau, Peter J. Murray, Markus A. Seeger, Brenda A. Schulman () and Bastian Bräuning ()
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J. Josephine Botsch: Max Planck Institute of Biochemistry
Roswitha Junker: Max Planck Institute of Biochemistry
Michèle Sorgenfrei: University of Zurich
Patricia P. Ogger: Max Planck Institute of Biochemistry
Luca Stier: Max Planck Institute of Biochemistry
Susanne Gronau: Max Planck Institute of Biochemistry
Peter J. Murray: Max Planck Institute of Biochemistry
Markus A. Seeger: University of Zurich
Brenda A. Schulman: Max Planck Institute of Biochemistry
Bastian Bräuning: Max Planck Institute of Biochemistry

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract Transmembrane E3 ligases play crucial roles in homeostasis. Much protein and organelle quality control, and metabolic regulation, are determined by ER-resident MARCH6 E3 ligases, including Doa10 in yeast. Here, we present Doa10/MARCH6 structural analysis by cryo-EM and AlphaFold predictions, and a structure-based mutagenesis campaign. The majority of Doa10/MARCH6 adopts a unique circular structure within the membrane. This channel is established by a lipid-binding scaffold, and gated by a flexible helical bundle. The ubiquitylation active site is positioned over the channel by connections between the cytosolic E3 ligase RING domain and the membrane-spanning scaffold and gate. Here, by assaying 95 MARCH6 variants for effects on stability of the well-characterized substrate SQLE, which regulates cholesterol levels, we reveal crucial roles of the gated channel and RING domain consistent with AlphaFold-models of substrate-engaged and ubiquitylation complexes. SQLE degradation further depends on connections between the channel and RING domain, and lipid binding sites, revealing how interconnected Doa10/MARCH6 elements could orchestrate metabolic signals, substrate binding, and E3 ligase activity.

Date: 2024
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DOI: 10.1038/s41467-023-44670-5

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