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Structure of KAP1 tripartite motif identifies molecular interfaces required for retroelement silencing.

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Oda, Shun-Ichiro 
Chong, Zheng-Shan 
McLaughlin, Stephen H  ORCID logo


Transcription of transposable elements is tightly regulated to prevent genome damage. KRAB domain-containing zinc finger proteins (KRAB-ZFPs) and KRAB-associated protein 1 (KAP1/TRIM28) play a key role in regulating retrotransposons. KRAB-ZFPs recognize specific retrotransposon sequences and recruit KAP1, inducing the assembly of an epigenetic silencing complex, with chromatin remodeling activities that repress transcription of the targeted retrotransposon and adjacent genes. Our biophysical and structural data show that the tripartite motif (TRIM) of KAP1 forms antiparallel dimers, which further assemble into tetramers and higher-order oligomers in a concentration-dependent manner. Structure-based mutations in the B-box 1 domain prevent higher-order oligomerization without significant loss of retrotransposon silencing activity, indicating that, in contrast to other TRIM-family proteins, self-assembly is not essential for KAP1 function. The crystal structure of the KAP1 TRIM dimer identifies the KRAB domain binding site in the coiled-coil domain near the dyad. Mutations at this site abolished KRAB binding and transcriptional silencing activity of KAP1. This work identifies the interaction interfaces in the KAP1 TRIM responsible for self-association and KRAB binding and establishes their role in retrotransposon silencing.



endogenous retrovirus, epigenetic silencing, transcriptional repressor, transposable element, ubiquitin E3 ligase, Amino Acid Sequence, Binding Sites, Chromatin, Chromatin Assembly and Disassembly, Cloning, Molecular, Crystallography, X-Ray, Epigenesis, Genetic, Escherichia coli, Gene Expression, Gene Silencing, Genetic Vectors, Humans, Models, Molecular, Protein Binding, Protein Conformation, alpha-Helical, Protein Conformation, beta-Strand, Protein Interaction Domains and Motifs, Protein Multimerization, Recombinant Proteins, Repressor Proteins, Retroelements, Sequence Alignment, Sequence Homology, Amino Acid, Transcription, Genetic, Tripartite Motif-Containing Protein 28

Journal Title

Proc Natl Acad Sci U S A

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Proceedings of the National Academy of Sciences


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Wellcome Trust (101908/Z/13/Z)
MRC (MR/S021604/1)
This work was supported by Wellcome Trust through Senior Research Fellowship 101908/Z/13/Z and PhD Studentship 205833/Z/16/Z.