Evidence map›Paper›PMID 42190653›Full record

ArticleMolecular cell2026

Design principles of a membrane-spanning ubiquitin ligase.

Carys Williams, Laura M Nocka, George Hedger, Pragya Parashara, Els Pardon, Naomi R Latorraca, Ganesh V Pusapati, Parijat Sarkar, Dorothy Lartey, Lei Gao and 10 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Molecular cell, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

2 citing papers in PubMed.

  1. Review
  2. Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

20 authors.

Carys WilliamsDivision of Structural Biology, Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
Laura M NockaDepartments of Biochemistry and Medicine, Stanford University School of Medicine, Stanford, CA, USA.
George HedgerDepartment of Life Sciences, Sir Ernst Chain Building, South Kensington Campus, Imperial College London, London, UK.
Pragya ParasharaDepartment of Biochemistry, School of Medicine, University of Washington, Seattle, WA, USA.
Els PardonVIB-VUB Center for Structural Biology, VIB, Pleinlaan 2, 1050 Brussels, Belgium; Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium.
Naomi R LatorracaDepartment of Molecular & Cell Biology, University of California, Berkeley, Berkeley, CA, USA; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA.
Ganesh V PusapatiDepartments of Biochemistry and Medicine, Stanford University School of Medicine, Stanford, CA, USA.
Parijat SarkarDepartments of Biochemistry and Medicine, Stanford University School of Medicine, Stanford, CA, USA.
Dorothy LarteyDepartment of Biochemistry, School of Medicine, University of Washington, Seattle, WA, USA.
Lei GaoDepartment of Biochemistry, School of Medicine, University of Washington, Seattle, WA, USA.
Ljiljana MilenkovicDepartments of Biochemistry and Medicine, Stanford University School of Medicine, Stanford, CA, USA.
Rod ChalkCentre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
Jan SteyaertVIB-VUB Center for Structural Biology, VIB, Pleinlaan 2, 1050 Brussels, Belgium; Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium.
Susan MarquseeDepartment of Molecular & Cell Biology, University of California, Berkeley, Berkeley, CA, USA; Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA; Chan Zuckerberg Biohub, San Francisco, CA, USA.
Loïc CarriqueDivision of Structural Biology, Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
J Fernando Bazanℏ bioconsulting, LLC, Stillwater, MN 55082, USA.
Sarah L RouseDepartment of Life Sciences, Sir Ernst Chain Building, South Kensington Campus, Imperial College London, London, UK.
Jennifer H KongDepartment of Biochemistry, School of Medicine, University of Washington, Seattle, WA, USA.
Christian SieboldDivision of Structural Biology, Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK. Electronic address: christian@strubi.ox.ac.uk.
Rajat RohatgiDepartments of Biochemistry and Medicine, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: rrohatgi@stanford.edu.

Funding

Translational Bioimaging Core Shared ResourceP30CA015704 · NCI · FRED HUTCHINSON CANCER RESEARCH CENTER · PI Eric Collisson · 1985 to 2026
$296.4M
Supplement application for an Olympus automated microscopeR35GM118082 · NIGMS · STANFORD UNIVERSITY · PI RAJAT ROHATGI · 2016 to 2026
$7.6M
A protein traffic control system that regulates left-right patterning and heart developmentR01HL157103 · NHLBI · STANFORD UNIVERSITY · PI GUNN, TERESA M, LO, CECILIA W. · 2021 to 2024
$2.9M
Sequence and Environmental Determinants of the Protein Energy LandscapeR35GM149319 · NIGMS · UNIVERSITY OF CALIFORNIA BERKELEY · PI SUSAN MARQUSEE · 2023 to 2026
$1.7M
Molecular mechanisms that regulate target cell sensitivity to Hedgehog morphogensR00GM132518 · NIGMS · UNIVERSITY OF WASHINGTON · PI KONG, JENNIFER · 2023 to 2025
$871k
Decoding Structural Determinants of Efficacy and Specificity in a GPCR SubfamilyR00GM148823 · NIGMS · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI Naomi Latorraca · 2025 to 2026
$498k
Molecular mechanisms that regulate target cell sensitivity to Hedgehog morphogensK99GM132518 · NIGMS · STANFORD UNIVERSITY · PI KONG, JENNIFER · 2019 to 2021
$281k
Decoding Structural Determinants of Efficacy and Specificity in a GPCR SubfamilyK99GM148823 · NIGMS · UNIVERSITY OF CALIFORNIA BERKELEY · PI LATORRACA, NAOMI · 2023 to 2024
$212k
NCI NIH HHS P30 CA015704NHLBI NIH HHS R01 HL157103NIGMS NIH HHS K99 GM132518NIGMS NIH HHS K99 GM148823NIGMS NIH HHS R00 GM132518NIGMS NIH HHS R00 GM148823NIGMS NIH HHS R35 GM118082NIGMS NIH HHS R35 GM149319Wellcome Trust
6 · The paper itself

Abstract

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.

Indexed as

Cell MembraneMembrane ProteinsSmoothened ReceptorUbiquitin-Protein LigasesAnimalsCiliaCryoelectron MicroscopyHedgehog ProteinsHEK293 CellsHumansModels, MolecularMutationSignal TransductionUbiquitinationHedgehog ProteinsMembrane ProteinsSmoothened ReceptorSMO protein, humanUbiquitin-Protein Ligasesbirth defectscryoelectron microscopyE3 ligaseGPCRHedgehog signalingmorphogensprimary ciliaSmoothenedtransmembrane receptorubiquitylation

Identifiers

PMID42190653
PMCPMC13234867

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.