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Cited by 7Ubiquitin and proteasome pathwaysDevelopmental Biology and Gene RegulationGenomics and Chromatin Dynamics

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Structural requirements for activity of Mind bomb1 in Notch signaling

Open access
Cao, Ruili, Gozlan, Oren, Airich, Alina, Tveriakhina, Lena, Zhou, Haixia, Jiang, Hanjie, Cole, Philip A., Aster, Jon C., Klein, Thomas, Sprinzak, David, Blacklow, Stephen C.·2024·Structure
DOI 10.1016/j.str.2024.07.011PMC PMC12094784

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Abstract

Mind bomb 1 (MIB1) is a RING E3 ligase that ubiquitinates Notch ligands, a necessary step for induction of Notch signaling. The structural basis for binding of the JAG1 ligand by the N-terminal region of MIB1 is known, yet how the ankyrin (ANK) and RING domains of MIB1 cooperate to catalyze ubiquitin transfer from E2∼Ub to Notch ligands remains unclear. Here, we show that the third RING domain and adjacent coiled coil region (ccRING3) drive MIB1 dimerization and that MIB1 ubiquitin transfer activity relies solely on ccRING3. We report X-ray crystal structures of a UbcH5B-ccRING3 complex and the ANK domain. Directly tethering the MIB1 N-terminal region to ccRING3 forms a minimal MIB1 protein sufficient to induce a Notch response in receiver cells and rescue mib knockout phenotypes in flies. Together, these studies define the functional elements of an E3 ligase needed for ligands to induce a Notch signaling response.

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Metadata

Authors
Cao, R., Gozlan, O., Airich, A., Tveriakhina, L., Zhou, H., Jiang, H., Cole, P. A., Aster, J. C., Klein, T., Sprinzak, D., & Blacklow, S. C.
Affiliations
  • Harvard University (US)
  • Tel Aviv University (IL)
  • Heinrich Heine University Düsseldorf (DE)
  • Brigham and Women's Hospital (US)
Corresponding author
Blacklow, Stephen C.
ORCID
Venue
Structure
Publisher
Elsevier BV
Published
2024-10
Volume
32
Issue
10
Pages
1667-1676.e5
ISSN
0969-2126 (ISSN-L)
DOI
10.1016/j.str.2024.07.011
PMC
PMC12094784
OpenAlex
W4401419802
Cited by
7
References
1
Citations by year
2026: 2 · 2025: 3 · 2024: 2
FWCI
0.95
Type
journal article
Language
en
Open access
Licence
Locations
  • Structure (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
Funders
  • Charles H. Revson Foundation
  • Springworks Therapeutics
  • Deutsche Forschungsgemeinschaft
  • United States-Israel Binational Science Foundation (2017245)
  • National Institutes of Health (CA74305)
  • Ludwig Center at Harvard
  • National Cancer Institute (R35CA220340, R01CA272484, R01CA074305)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords
Notch signaling, RING E3 ubiquitin ligase, protein dimerization, UbcH5b, ankyrin domain, crystal structure, protein structure-function relationship, Drosophila

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