8QFB
Crystal structure of human MPP8 C-terminal region (residues 565-860)
Summary for 8QFB
| Entry DOI | 10.2210/pdb8qfb/pdb |
| Descriptor | M-phase phosphoprotein 8 (1 entity in total) |
| Functional Keywords | transcriptional regulation, epigenetic silencing, antiviral response, genome stability, histone h3 lysine 9 methylation (h3k9me3), transposable element (te), long interspersed nuclear element-1 (line-1), rna-binding protein, human silencing hub (hush) complex, transcription |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 8 |
| Total formula weight | 295360.44 |
| Authors | Prigozhin, D.M.,Modis, Y. (deposition date: 2023-09-04, release date: 2024-09-11, Last modification date: 2024-12-25) |
| Primary citation | Nikolopoulos, N.,Oda, S.I.,Prigozhin, D.M.,Modis, Y. Structure and Methyl-lysine Binding Selectivity of the HUSH Complex Subunit MPP8. J.Mol.Biol., 437:168890-168890, 2024 Cited by PubMed 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. AlphaFold3 modeling of the MPP8-TASOR complex predicts that a SPOC domain and a domain with a novel fold in TASOR form extended interaction interfaces with the MPP8 CTD. Point mutations at these interfaces resulted in loss of HUSH-dependent transcriptional repression in a cell-based reporter assay, validating the AlphaFold3 model. The MPP8 chromodomain, known to bind the repressive mark H3K9me3, bound 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. PubMed: 39638237DOI: 10.1016/j.jmb.2024.168890 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.04 Å) |
Structure validation
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