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PreprintCited by 6Genomics and Chromatin DynamicsEpigenetics and DNA MethylationChromosomal and Genetic Variations

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Structure and methyl-lysine binding selectivity of the HUSH complex subunit MPP8

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Nikolopoulos, Nikos, Oda, Shun-ichiro, Prigozhin, Daniil M., Modis, Yorgo·2023·Journal of Molecular Biology
DOI 10.1101/2023.12.21.572340PMC PMC7618375

Preprint — published as 10.1016/j.jmb.2024.168890

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Abstract

The Human Silencing Hub (HUSH) guards the genome from the pathogenic effects of retroelement expression. Composed of MPP8, TASOR, and Periphilin-1, HUSH recognizes actively transcribed retrotransposed sequences by the presence of long (>1.5-kb) nascent transcripts without introns. HUSH recruits effectors that alter chromatin structure, degrade transcripts, and deposit transcriptionally repressive epigenetic marks. Here, we report the crystal structure of the C-terminal domain (CTD) of MPP8 necessary for HUSH activity. The MPP8 CTD consists of five ankyrin repeats followed by a domain with structural homology to the PINIT domains of Siz/PIAS-family SUMO E3 ligases. AlphaFold-Multimer modeling predicts that the MPP8 CTD forms extended interaction interfaces with a SPOC domain and a domain with a novel fold in TASOR. The MPP8 chromodomain, known to bind the repressive mark H3K9me3, binds with similar or higher affinity to sequences in the H3K9 methyltransferase subunits SETDB1, ATF7IP, G9a, and GLP. Hence, MPP8 promotes heterochromatinization by recruiting H3K9 methyltransferases. Our work identifies novel structural elements in MPP8 required for HUSH complex assembly and silencing, thereby fulfilling vital functions in controlling retrotransposons.

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Metadata

Authors
Nikolopoulos, N., Oda, S.-I., Prigozhin, D. M., & Modis, Y.
Affiliations
  • MRC Laboratory of Molecular Biology (GB)
  • Lawrence Berkeley National Laboratory (US)
Corresponding author
Modis, Yorgo
ORCID
Venue
Journal of Molecular Biology
Publisher
openRxiv
Published
2023-12-21
Volume
437
Issue
2
Pages
168890-168890
ISSN
0022-2836 (ISSN-L)
DOI
10.1101/2023.12.21.572340
PMC
PMC7618375
OpenAlex
W4405127957
Cited by
6
References
1
Citations by year
2026: 5 · 2025: 1
FWCI
0.81
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Journal of Molecular Biology (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, other-oa)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (acceptedVersion, cc-by)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
  • Apollo (cc-by)
Funders
  • Wellcome Trust (217191/Z/19/Z, 217191, 101908, 101908/B/13/Z, 101908/Z/13/Z)
  • Diamond Light Source
  • UK Research and Innovation (MX21426)
  • Medical Research Council (MR/X012182/1)
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 › Biochemistry, Genetics and Molecular Biology › Genetics › Chromosomal and Genetic Variations
Keywords
HUSH complex, MPP8, retrotransposon silencing, chromodomain, H3K9me3, chromatin silencing, ankyrin repeats, heterochromatinization, H3K9 methyltransferase, transcriptional repression, crystal structure, AlphaFold3
MeSH terms
Protein Domains, Humans, Lysine, Models, Molecular, Phosphoproteins, Protein Binding, Crystallography, X-Ray

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