Structure and functional mapping of the KRAB‐KAP1 repressor complex


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Article
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Abstract

jats:titleAbstract</jats:title>jats:pTransposable 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.</jats:p>

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Keywords
EMBO09, EMBO40, Article, Articles, CRISPRi, H3K9me3, heterochromatin, Krüppel‐associated box, Transposable element
Journal Title
The EMBO Journal
Conference Name
Journal ISSN
0261-4189
1460-2075
Volume Title
Publisher
Springer Science and Business Media LLC
Sponsorship
Svenska Sällskapet för Medicinsk Forskning (SSMF) (S19‐0100)
UKRI¦Medical Research Council (MRC) (MR/S021604/1)
Vetenskapsrådet (VR) (2021‐03494)
Wellcome Trust (WT) (217191/Z/19/Z, 205833/Z/16/Z)