8QFB

Crystal structure of human MPP8 C-terminal region (residues 565-860)

8QFB の概要

• エントリーDOI: 10.2210/pdb8qfb/pdb
• 分子名称: M-phase phosphoprotein 8 (1 entity in total)
• 機能のキーワード: 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
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 295360.44

構造登録者

Prigozhin, D.M.,Modis, Y. (登録日: 2023-09-04, 公開日: 2024-09-11, 最終更新日: 2024-12-25)

主引用文献

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

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: 39638237
DOI: 10.1016/j.jmb.2024.168890

実験手法

X-RAY DIFFRACTION (3.04 Å)