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Structural Requirements for Activity of Mind bomb1 in Notch Signaling
Open accessPreprint — published as 10.1016/j.str.2024.07.011 · Paper page
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 of MIB1 (ccRING3) drives MIB1 dimerization and that ubiquitin transfer activity of MIB1 relies solely on RING3. We report x-ray crystal structures of a UbcH5B-ccRING3 complex as a fusion protein and of the ANK region. Directly tethering the N-terminal region to ccRING3 forms a minimal MIB1 protein, which is sufficient to induce a Notch response in receiver cells. 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., Tveriakhina, L., Zhou, H., Jiang, H., Cole, P. A., Aster, J. C., Sprinzak, D., & Blacklow, S. C.
- Affiliations
- Harvard University (US)
- Tel Aviv University (IL)
- Brigham and Women's Hospital (US)
- Corresponding author
- Blacklow, Stephen C.
- ORCID
- Venue
- Structure
- Publisher
- openRxiv
- Published
- 2024-03-03
- Volume
- 32
- Issue
- 10
- Pages
- 1667-1676.e5
- ISSN
- 0969-2126 (ISSN-L)
- 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
- bronze
- doi.org
- 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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