ArticleThe Journal of biological chemistry2014
Disulfide bond requirements for active Wnt ligands.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers.
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Who cites it
58 citing papers in PubMed, 100 citations in OpenAlex.
- Genome-Wide Identification and Characterization of theBiology · 2026Article
- Genetic screening identifies WNT5A/RYK as a determinant of extracellular vesicle fate.Science advances · 2026Article
- Interpretable machine learning uncovers structural determinants of Wnt-Wntless binding specificity from atomistic simulations.Communications chemistry · 2026Article
- WNT5a export onto extracellular vesicles studied at single-molecule and single-vesicle resolution.The FEBS journal · 2025Article
- A homozygous human WNT11 variant is associated with laterality, heart and renal defects.Disease models & mechanisms · 2025Article
- Mechanistic insights into Wnt-β-catenin pathway activation and signal transduction.Nature reviews. Molecular cell biology · 2025Review
- The Cys-His-Gly triplet within the WNT motif is essential for Wnt16 functionmicroPublication biology · 2025Article
- Identification of the Wnt signal peptide that directs secretion on extracellular vesicles.Science advances · 2024Article
- Synthesis and Frizzled-receptor binding of a WNT5A hairpin-3 peptide.Chemical communications (Cambridge, England) · 2024Article
- Multi-omics analyses reveal aberrant differentiation trajectory with WNT1 loss-of-function in type XV osteogenesis imperfecta.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2024Article
- Wnt7b acts in concert with Wnt5a to regulate tissue elongation and planar cell polarity via noncanonical Wnt signaling.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- In vitro evolution and whole genome analysis to study chemotherapy drug resistance in haploid human cells.Scientific reports · 2024Article
- Exome sequencing identified mutations in the WNT1 and COL1A2 genes in osteogenesis imperfecta cases.Molecular biology reports · 2024Article
- Alternative Wnt-signaling axis leads to a break of oncogene-induced senescence.Cell death & disease · 2024Article
- Article
- Hydrogen sulfide suppresses HMedical oncology (Northwood, London, England) · 2023Article
- Genotypic and Phenotypic Spectrum and Pathogenesis of WNT1 Variants in a Large Cohort of Patients With OI/Osteoporosis.The Journal of clinical endocrinology and metabolism · 2023Article
- Evidence for a Dual-Pathway, 2-Hit Genetic Model for Focal Cortical Dysplasia and Epilepsy.Neurology. Genetics · 2022Article
- Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome: WNT signaling perturbation and phenotypic variability.HGG advances · 2022Article
- The regulatory role of endoplasmic reticulum chaperone proteins in neurodevelopment.Frontiers in neuroscience · 2022Review
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
Secreted Wnt lipoproteins are cysteine-rich and lipid-modified morphogens that bind to the Frizzled (FZD) receptor and LDL receptor-related protein 6 (LRP6). Wnt engages FZD through protruding thumb and index finger domains, which are each assembled from paired β strands secured by disulfide bonds and grasp two sides of the FZD ectodomain. The importance of Wnt disulfide bonds has been assumed but uncharacterized. We systematically analyzed cysteines and associated disulfide bonds in the prototypic Wnt3a. Our data show that mutation of any individual cysteine of Wnt3a results in covalent Wnt oligomers through ectopic intermolecular disulfide bond formation and diminishes/abolishes Wnt signaling. Although individual cysteine mutations in the amino part of the saposin-like domain and in the base of the index finger are better tolerated and permit residual Wnt3a secretion/activity, those in the amino terminus, the thumb, and at the tip of the index finger are incompatible with secretion and/or activity. A few select double cysteine mutants based on the disulfide bond pattern restore Wnt secretion/activity. Further, a double cysteine mutation at the index finger tip results in a Wnt3a with normal secretion but minimal FZD binding and dominant negative properties. Our results experimentally validate predictions from the Wnt crystal structure and highlight critical but different roles of the saposin-like and cytokine-like domains, including the thumb and the index finger in Wnt folding/secretion and FZD binding. Finally, we modified existing expression vectors for 19 epitope-tagged human WNT proteins by removal of a tag-supplied ectopic cysteine, thereby generating tagged WNT ligands active in canonical and non-canonical signaling.
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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.