ArticleJournal of molecular biology2016
Multiple Weak Linear Motifs Enhance Recruitment and Processivity in SPOP-Mediated Substrate Ubiquitination.
Article in Journal of molecular biology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 64 citations in OpenAlex.
- Short linear motifs-underexplored players drivingMicrobiology spectrum · 2026Article
- Large-scale quaternary structural transitions underlie gain of function of SPOP cancer mutations.Molecular cell · 2026Article
- Disordered but rhythmic-the role of intrinsic protein disorder in eukaryotic circadian timing.FEBS letters · 2026Review
- GLI3 in cancer: a context-dependent regulator with diagnostic, prognostic, and therapeutic potential.Frontiers in immunology · 2026Review
- Cancer degronopathies and protein-fate biomarkers in drug resistance and cancer progression: signalling mechanisms, measurement and translational limits.Frontiers in cell and developmental biology · 2026Review
- Article
- The equilibrium between two quaternary assembly states determines the activity of SPOP and its cancer mutants.bioRxiv : the preprint server for biology · 2025Article
- Sequence rules for a long SPOP-binding degron required for protein ubiquitylation.The Biochemical journal · 2025Article
- Cul3 substrate adaptor SPOP targets Nup153 for degradation.Molecular biology of the cell · 2025Article
- SPOP-mediated RIPK3 destabilization desensitizes LPS/sMAC/zVAD-induced necroptotic cell death.Cellular and molecular life sciences : CMLS · 2024Article
- Higher-order SPOP assembly reveals a basis for cancer mutant dysregulation.Molecular cell · 2023Article
- Article
- Review
- The evolving landscape of prostate cancer somatic mutations.The Prostate · 2022Review
- Counting Degrons: Lessons From Multivalent Substrates for Targeted Protein Degradation.Frontiers in physiology · 2022Review
- The Role of Ubiquitin in Regulating Stress Granule Dynamics.Frontiers in physiology · 2022Review
- Transcription Regulators and Membraneless Organelles Challenges to Investigate Them.International journal of molecular sciences · 2021Review
- SPOP mutation induces replication over-firing by impairing Geminin ubiquitination and triggers replication catastrophe upon ATR inhibition.Nature communications · 2021Article
- ATM-phosphorylated SPOP contributes to 53BP1 exclusion from chromatin during DNA replication.Science advances · 2021Article
- Article
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Authors and funding
10 authors at 1 institution in 1 country.
Funding
Abstract
Primary sequence motifs, with millimolar affinities for binding partners, are abundant in disordered protein regions. In multivalent interactions, such weak linear motifs can cooperate to recruit binding partners via avidity effects. If linear motifs recruit modifying enzymes, optimal placement of weak motifs may regulate access to modification sites. Weak motifs may thus exert physiological relevance stronger than that suggested by their affinities, but molecular mechanisms of their function are still poorly understood. Herein, we use the N-terminal disordered region of the Hedgehog transcriptional regulator Gli3 (Gli3(1-90)) to determine the role of weak motifs encoded in its primary sequence for the recruitment of its ubiquitin ligase CRL3(SPOP) and the subsequent effect on ubiquitination efficiency. The substrate adaptor SPOP binds linear motifs through its MATH (meprin and TRAF homology) domain and forms higher-order oligomers through its oligomerization domains, rendering SPOP multivalent for its substrates. Gli3 has multiple weak SPOP binding motifs. We map three such motifs in Gli3(1-90), the weakest of which has a millimolar dissociation constant. Multivalency of ligase and substrate for each other facilitates enhanced ligase recruitment and stimulates Gli3(1-90) ubiquitination in in vitro ubiquitination assays. We speculate that the weak motifs enable processivity through avidity effects and by providing steric access to lysine residues that are otherwise not prioritized for polyubiquitination. Weak motifs may generally be employed in multivalent systems to act as gatekeepers regulating post-translational modification.
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Registered trials
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.