ArticleeLife2020
Multiplexed measurement of variant abundance and activity reveals VKOR topology, active site and human variant impact.
Article in eLife, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 60 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
60 citing papers in PubMed, 101 citations in OpenAlex.
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- Allostery is a widespread cause of loss-of-function variant pathogenicity.Nature communications · 2026Article
- VEFill: accurate and generalizable deep mutational scanning score imputation across protein domains.Molecular systems biology · 2026Article
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- The evolving landscape of pharmacogenomics: Current achievements and future directions.Pharmacological reviews · 2026Review
- Deconvolving mutation effects on protein stability and function with disentangled protein language models.bioRxiv : the preprint server for biology · 2026Article
- A near-complete map of human cytosolic degrons and their relevance for disease.Science advances · 2026Article
- Multiplexed assays of variant effect for clinical variant interpretation.Nature reviews. Genetics · 2026Review
- BOGO: A Proteome-Wide Gene Overexpression Platform for Discovering Rational Cancer Combination Therapies.bioRxiv : the preprint server for biology · 2025Article
- Multiplex and multimodal mapping of variant effects in secreted proteins via MultiSTEP.Nature structural & molecular biology · 2025Article
- A probabilistic graphical model for estimating selection coefficients of nonsynonymous variants from human population sequence data.Nature communications · 2025Article
- Translating pharmacogenomic sequencing data into drug response predictions-How to interpret variants of unknown significance.British journal of clinical pharmacology · 2025Review
- Multiplex, multimodal mapping of variant effects in secreted proteins.bioRxiv : the preprint server for biology · 2025Article
- Article
- SSEmb: A joint embedding of protein sequence and structure enables robust variant effect predictions.Nature communications · 2024Article
- Deep mutational scanning of CYP2C19 in human cells reveals a substrate specificity-abundance tradeoff.Genetics · 2024Article
- Multiplexed profiling of intracellular protein abundance, activity, interactions and druggability with LABEL-seq.Nature methods · 2024Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
12 authors at 4 institutions in 2 countries.
Funding
Abstract
Vitamin K epoxide reductase (VKOR) drives the vitamin K cycle, activating vitamin K-dependent blood clotting factors. VKOR is also the target of the widely used anticoagulant drug, warfarin. Despite VKOR's pivotal role in coagulation, its structure and active site remain poorly understood. In addition, VKOR variants can cause vitamin K-dependent clotting factor deficiency or alter warfarin response. Here, we used multiplexed, sequencing-based assays to measure the effects of 2,695 VKOR missense variants on abundance and 697 variants on activity in cultured human cells. The large-scale functional data, along with an evolutionary coupling analysis, supports a four transmembrane domain topology, with variants in transmembrane domains exhibiting strongly deleterious effects on abundance and activity. Functionally constrained regions of the protein define the active site, and we find that, of four conserved cysteines putatively critical for function, only three are absolutely required. Finally, 25% of human VKOR missense variants show reduced abundance or activity, possibly conferring warfarin sensitivity or causing disease.
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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.