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TitleDesign principles of a membrane-spanning ubiquitin ligase.
Journal, issue, pagesMol Cell, Vol. 86, Issue 11, Page 2207-2222.e16, Year 2026
Publish dateJun 4, 2026
AuthorsCarys Williams / Laura M Nocka / George Hedger / Pragya Parashara / Els Pardon / Naomi R Latorraca / Ganesh V Pusapati / Parijat Sarkar / Dorothy Lartey / Lei Gao / Ljiljana Milenkovic / Rod Chalk / Jan Steyaert / Susan Marqusee / Loïc Carrique / J Fernando Bazan / Sarah L Rouse / Jennifer H Kong / Christian Siebold / Rajat Rohatgi /
PubMed AbstractReceptor-type E3 ubiquitin ligases enable extracellular signals to control ubiquitylation in the cytoplasm, playing widespread roles in development, metabolism, and immunity. Using cryoelectron ...Receptor-type E3 ubiquitin ligases enable extracellular signals to control ubiquitylation in the cytoplasm, playing widespread roles in development, metabolism, and immunity. Using cryoelectron microscopy, integrated with biophysical and functional studies, we visualized a human E3 complex composed of two transmembrane proteins, MEGF8 and MOSMO, and the intracellular RING-family protein MGRN1. This MEGF8-MOSMO-MGRN1 (MMM) complex attenuates Hedgehog signaling by ubiquitylating Smoothened (SMO), a G-protein-coupled receptor (GPCR) that transduces morphogen signals. A long helix in the MMM complex engages SMO using an intramembrane degron and extends into the cytoplasm to suspend an activated and precisely oriented RING domain below the plasma membrane. This architecture enables ubiquitylation of the cytoplasmic surface of SMO, reducing SMO abundance at primary cilia. Our structure provides insights into MEGF8 mutations, which cause multi-organ birth defects, and defines a paradigm for how transmembrane E3 ligases control the cell surface abundance of GPCRs and other signaling receptors.
External linksMol Cell / PubMed:42190653 / PubMed Central
MethodsEM (single particle)
Resolution2.65 - 4.66 Å
Structure data

53313

9qqs

EMDB-53313, PDB-9qqs:
Structure of the MEGF8-MOSMO complex with nanobody 270 (Focused refinement)
Method: EM (single particle) / Resolution: 2.65 Å

EMDB-53321: Focused refinement of the MGRN1 ubiquitin ligase in complex with MEGF8, MOSMO and nanobody 270
Method: EM (single particle) / Resolution: 3.33 Å

EMDB-53322: Structure of the MMM ubiquitin ligase complex with nanobody 270 (Consensus map)
Method: EM (single particle) / Resolution: 2.74 Å

53323

9qru

EMDB-53323, PDB-9qru:
Cryo-EM structure of the MMM ubiquitin ligase complex with nanobody 270 (Composite map)
Method: EM (single particle) / Resolution: 3.03 Å

EMDB-53327: Structure of the helix-stabilized MMM ubiquitin ligase complex with nanobody 270 (Consensus map)
Method: EM (single particle) / Resolution: 3.14 Å

EMDB-53328: Focused refinement of the MGRN1 ubiquitin ligase in complex with helix-stabilized MEGF8, MOSMO and nanobody 270
Method: EM (single particle) / Resolution: 4.41 Å

53329

9qs6

EMDB-53329, PDB-9qs6:
Cryo-EM structure of the helix-stabilized MMM ubiquitin ligase complex with nanobody 270 (Composite map)
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-53336: Focused refinement of the MEGF8-MOSMO complex with nanobody 992
Method: EM (single particle) / Resolution: 3.39 Å

EMDB-53337: Focused refinement of the MEGF8 and MOSMO extracellular domains with nanobody 992
Method: EM (single particle) / Resolution: 3.29 Å

EMDB-53338: Focused refinement of the MGRN1 ubiquitin ligase in complex with MEGF8, MOSMO and nanobody 992
Method: EM (single particle) / Resolution: 4.66 Å

EMDB-53339: Structure of the MMM ubiquitin ligase complex with nanobody 992 (Consensus map)
Method: EM (single particle) / Resolution: 3.58 Å

53340

9qsh

EMDB-53340, PDB-9qsh:
Cryo-EM structure of the MMM ubiquitin ligase complex with nanobody 992 (Composite map)
Method: EM (single particle) / Resolution: 3.5 Å

53367

9qty

EMDB-53367, PDB-9qty:
Cryo-EM structure of the binary MEGF8-MOSMO complex with nanobody 270
Method: EM (single particle) / Resolution: 2.98 Å

EMDB-57249: Focused refinement of the helix-stabilized MEGF8-MOSMO complex with nanobody 270
Method: EM (single particle) / Resolution: 2.95 Å

Chemicals

ChemComp-PLM:
PALMITIC ACID

PDB-1jax:
Structure of Coenzyme F420H2:NADP+ Oxidoreductase (FNO)

ChemComp-HOH:
WATER

ChemComp-ZN:
Unknown entry

Source
  • homo sapiens (human)
  • lama glama (llama)
KeywordsMEMBRANE PROTEIN / E3 Ubiquitin Ligase / Hedgehog Signaling / Single-pass Membrane Protein / Membrane Protein Complex / Smoothened / Tetraspanin / Cell Surface Receptor / Primary Cilium / Morphogen / Signal Transduction / Human / Carpenter Syndrome / Cancer / Nanobody / Palmitoylation / GDN

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