Structure and functional mapping of the KRAB‐KAP1 repressor complex
Open accessPublished version of a preprint
Abstract
Transposable elements are a genetic reservoir from which new genes and regulatory elements can emerge. However, expression of transposable elements can be pathogenic and is therefore tightly controlled. KRAB domain-containing zinc finger proteins (KRAB-ZFPs) recruit the co-repressor KRAB-associated protein 1 (KAP1/TRIM28) to regulate many transposable elements, but how KRAB-ZFPs and KAP1 interact remains unclear. Here, we report the crystal structure of the KAP1 tripartite motif (TRIM) in complex with the KRAB domain from a human KRAB-ZFP, ZNF93. Structure-guided mutations in the KAP1-KRAB binding interface abolished repressive activity in an epigenetic transcriptional silencing assay. Deposition of H3K9me3 over thousands of loci is lost genome-wide in cells expressing a KAP1 variant with mutations that abolish KRAB binding. Our work identifies and functionally validates the KRAB-KAP1 molecular interface, which is critical for a central transcriptional control axis in vertebrates. In addition, the structure-based prediction of KAP1 recruitment efficiency will enable optimization of KRABs used in CRISPRi.
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Flagged first, then by citations
- Authors
- Stoll, G. A., Pandiloski, N., Douse, C. H., & Modis, Y.
- Affiliations
- MRC Laboratory of Molecular Biology (GB)
- Lund University (SE)
- Corresponding author
- Modis, Yorgo
- Venue
- The EMBO Journal
- Published
- 2022-11-07
- Volume
- 41
- Issue
- 24
- Pages
- e111179-e111179
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC9753469
- OpenAlex
- W4308368958
- Cited by
- 50
- References
- 11
- Citations by year
- 2026: 15 · 2025: 18 · 2024: 10 · 2023: 6 · 2022: 1
- FWCI
- 2.86
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- The EMBO Journal (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Apollo (University of Cambridge) (submittedVersion, cc-by-nc-nd)
- Apollo
- Funders
- Svenska Sällskapet för Medicinsk Forskning (S19‐0100)
- UKRI¦Medical Research Council (MR/S021604/1)
- Vetenskapsrådet (2021‐03494)
- Wellcome Trust (217191/Z/19/Z, 205833/Z/16/Z)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
- Keywords
- KRAB domain, zinc finger proteins, transposon silencing, transcriptional repression, H3K9me3, epigenetic silencing, protein-protein interfaces, CRISPR interference, structure-guided mutagenesis
- MeSH terms
- Tripartite Motif-Containing Protein 28, Animals, DNA Transposable Elements, Gene Expression Regulation, Humans, Repressor Proteins, Zinc Fingers, Epigenesis, Genetic
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