Keio University Human Biology-Microbiome-Quantum Research Center (WPI-Bio2Q) held a seminar as follows.

16:00 -17:00, February 26, 2026

Venue:
3F Meeting Room Center for Integrated Medical Research, Shinanomachi Campus, Keio University

Speaker:
Carys Williams, Ph.D.
Postdoctoral Fellow at MRC Laboratory of Molecular Biology
Cambridge, UK

Title: “Design principles of a membrane-spanning ubiquitin ligase”

Abstruct:
Ubiquitination regulates protein stability, interactions, and localisation in eukaryotic cells. With over 600 E3 ligases determining ubiquitination specificity, they are central to targeted protein degradation strategies in drug development. Membrane-spanning E3 ligases that target receptors are particularly intriguing because they enable extracellular signals to modulate ubiquitination in the cytoplasm, influencing development, metabolism, and immunity. Despite the critical roles of membrane-spanning E3s across development and physiology, no structural information is available for these E3 ligases in their membrane-embedded form.

Recent advances in cryogenic electron microscopy (cryo-EM) allow membrane proteins to be visualised at near-atomic resolution in near-native environments, overcoming challenges of instability and conformational heterogeneity. Using cryo-EM together with biophysical and functional studies, we determined the structure of an E3 ligase complex composed of two transmembrane proteins, MEGF8 and MOSMO, and the intracellular RING-family protein MGRN1. This MEGF8-MOSMO-MGRN1 (MMM) complex attenuates Hedgehog signalling by ubiquitinating Smoothened (SMO), a G-protein coupled receptor that transduces morphogen signals. A long helix in the MMM complex engages SMO and extends into the cytoplasm, positioning an activated RING domain precisely beneath the plasma membrane. This architecture enables ubiquitination of SMO’s cytoplasmic surface, reducing SMO abundance at primary cilia and fine-tuning signalling during development. Our findings reveal fundamental principles of receptor-type E3 ligase assembly and explain how MEGF8 mutations lead to complex multi-organ birth defects in humans.