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Structure and functional mapping of the KRAB‐KAP1 repressor complex
DOI:
10.15252/embj.2022111179
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
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
Discipline Tags:
Genetics
Structural biology
Life Sciences & Biotech
Technical Tags:
Diffraction
Macromolecular Crystallography (MX)