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Structure and functional mapping of the KRAB‐KAP1 repressor complex

DOI: 10.15252/embj.2022111179 DOI Help

Authors: Guido A. Stoll (University of Cambridge) , Ninoslav Pandiloski (Lund University) , Christopher H. Douse (Lund University) , Yorgo Modis (University of Cambridge)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: The Embo Journal , VOL 55

State: Published (Approved)
Published: November 2022
Diamond Proposal Number(s): 21426

Open Access Open Access

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.

Journal Keywords: CRISPRi; H3K9me3; heterochromatin; Krüppel-associated box; Transposable element

Diamond Keywords: Epigenetics

Subject Areas: Biology and Bio-materials


Instruments: I04-Macromolecular Crystallography

Added On: 09/11/2022 11:09

Documents:
The EMBO Journal - 2022 - Stoll - Structure and functional mapping of the KRAB‐KAP1 repressor complex.pdf

Discipline Tags:

Genetics Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)