ArticleNature communications2024
Doa10/MARCH6 architecture interconnects E3 ligase activity with lipid-binding transmembrane channel to regulate SQLE.
Article in Nature communications, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 14 citations in OpenAlex.
- Review
- Design principles of a membrane-spanning ubiquitin ligase.Molecular cell · 2026Article
- Genetic dissection of rapid proteolysis identifies TXNDC15 as a key factor of ERAD and lipid homeostasis.bioRxiv : the preprint server for biology · 2026Article
- "Design principles of a membrane-spanning ubiquitin ligase".bioRxiv : the preprint server for biology · 2025Article
- Illuminating ubiquitination mechanisms: How cryo-EM has shed light on Cullin RING E3 ligase function.Current opinion in structural biology · 2025Review
- The Role of Cholesterol Metabolism and Its Regulation in Tumor Development.Cancer medicine · 2025Review
- Genome-Wide Association Study of Body Size Traits in Luning Chickens Using Whole-Genome Sequencing.Animals : an open access journal from MDPI · 2025Article
- Stabilization of SQLE mRNA by WTAP/FTO/IGF2BP3-dependent manner in HGSOC: implications for metabolism, stemness, and progression.Cell death & disease · 2024Article
- Determinants of chemoselectivity in ubiquitination by the J2 family of ubiquitin-conjugating enzymes.The EMBO journal · 2024Article
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Authors and funding
10 authors at 2 institutions in 2 countries.
Funding
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.
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