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Structures of SPOP-Substrate Complexes: Insights into Molecular Architectures of BTB-Cul3 Ubiquitin Ligases
Open accessAbstract
In the largest E3 ligase subfamily, Cul3 binds a BTB domain, and an associated protein-interaction domain such as MATH recruits substrates for ubiquitination. Here, we present biochemical and structural analyses of the MATH-BTB protein, SPOP. We define a SPOP-binding consensus (SBC) and determine structures revealing recognition of SBCs from the phosphatase Puc, the transcriptional regulator Ci, and the chromatin component MacroH2A. We identify a dimeric SPOP-Cul3 assembly involving a conserved helical structure C-terminal of BTB domains, which we call "3-box" due to its facilitating Cul3 binding and its resemblance to F-/SOCS-boxes in other cullin-based E3s. Structural flexibility between the substrate-binding MATH and Cul3-binding BTB/3-box domains potentially allows a SPOP dimer to engage multiple SBCs found within a single substrate, such as Puc. These studies provide a molecular understanding of how MATH-BTB proteins recruit substrates to Cul3 and how their dimerization and conformational variability may facilitate avid interactions with diverse substrates.
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“BTB-containing E3 ligases are typically distinguished by the presence of a 3-box motif that enables high-affinity binding of Cullin 3 (refs 74,75 ).”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [75]
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Metadata
- Authors
- Zhuang, M., Calabrese, M. F., Liu, J., Waddell, M. B., Nourse, A., Hammel, M., Miller, D. J., Walden, H., Duda, D. M., Seyedin, S. N., Hoggard, T., Harper, J. W., White, K. P., & Schulman, B. A.
- Affiliations
- St. Jude Children's Research Hospital (US)
- University of Chicago (US)
- Lawrence Berkeley National Laboratory (US)
- University of Wisconsin System (US)
- Harvard University (US)
- Corresponding author
- Schulman, Brenda A.
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2009-10
- Volume
- 36
- Issue
- 1
- Pages
- 39-50
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC2847577
- OpenAlex
- W1993550226
- Cited by
- 486
- References
- 60
- Citations by year
- 2026: 29 · 2025: 38 · 2024: 27 · 2023: 35 · 2022: 39 · 2021: 50 · 2020: 45 · 2019: 32 · 2018: 25 · 2017: 28 · 2016: 23 · 2015: 25 · 2014: 28 · 2013: 24 · 2012: 14
- FWCI
- 4.66
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute (DRG 2021-9)
- National Cancer Institute (CA92584, P01CA092584, P30CA021765)
- National Institute of General Medical Sciences (R01GM070565, R01GM069530, GM070565)
- National Center for Research Resources (RR 15301, P41RR015301)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
- Keywords
- SPOP, BTB domain, CUL3, E3 ubiquitin ligase, MATH domain, substrate recognition, macroH2A, protein dimerization, SOCS box
- MeSH terms
- Amino Acid Sequence, Animals, DNA-Binding Proteins, Drosophila melanogaster, Histones, Humans, Models, Molecular, Mutation, Nuclear Proteins, Peptide Fragments, Phosphoprotein Phosphatases, Protein Binding, Recombinant Fusion Proteins, Repressor Proteins, Transcription Factors, Consensus Sequence, Crystallography, X-Ray, Molecular Chaperones, Protein Structure, Quaternary, Drosophila Proteins, Ubiquitin-Protein Ligases, Cullin Proteins, Adaptor Proteins, Signal Transducing, Protein Interaction Domains and Motifs, Ubiquitination, Protein Multimerization, Co-Repressor Proteins
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