1. Structural Biology and Molecular Biophysics
Download icon

Structural basis for histone variant H3tK27me3 recognition by PHF1 and PHF19

  1. Cheng Dong
  2. Reiko Nakagawa
  3. Kyohei Oyama
  4. Yusuke Yamamoto
  5. Weilian Zhang
  6. Aiping Dong
  7. Yanjun Li
  8. Yuriko Yoshimura
  9. Hiroyuki Kamiya
  10. Jun-ichi Nakayama
  11. Jun Ueda
  12. Jinrong Min  Is a corresponding author
  1. Tianjin Medical University, China
  2. RIKEN, Japan
  3. Asahikawa Medical University, Japan
  4. University of Toronto, Canada
  5. National Institute for Basic Biology, Japan
  6. National Institute of Basic Biology, Japan
Research Article
  • Cited 5
  • Views 1,187
  • Annotations
Cite this article as: eLife 2020;9:e58675 doi: 10.7554/eLife.58675

Abstract

The PRC2 (Polycomb repressive complex 2) complex is a multi-component histone H3K27 methyltransferase, best known for silencing Hox genes during embryonic development. The Polycomb-like proteins PHF1, MTF2 and PHF19 are critical components of PRC2 by stimulating its catalytic activity in embryonic stem (ES) cells. The Tudor domains of PHF1/19 have been previously shown to be readers of H3K36me3 in vitro. However, some other studies suggest that PHF1 and PHF19 co-localize with the H3K27me3 mark, but not H3K36me3 in cells. Here, we provide further evidence that PHF1 co-localizes with H3t in testis, and its Tudor domain preferentially binds to H3tK27me3 over canonical H3K27me3 in vitro. Our complex structures of the Tudor domains of PHF1 and PHF19 with H3tK27me3 shed light on the molecular basis for preferential recognition of H3tK27me3 by PHF1 and PHF19 over canonical H3K27me3, implicating that H3tK27me3 might be a physiological ligand of PHF1/19.

Data availability

Diffraction data have been deposited in PDB under the accession codes 6WAT, 6WAU, 6WAV

The following data sets were generated

Article and author information

Author details

  1. Cheng Dong

    Department of Biochemistry and Molecular Biology, Tianjin Medical University, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.

  2. Reiko Nakagawa

    Laboratory for Phyloinformatics, RIKEN, Kobe, Japan
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6178-2945

  3. Kyohei Oyama

    Department of Cardiac Surgery, Asahikawa Medical University, Asahikawa, Japan
    Competing interests
    The authors declare that no competing interests exist.

  4. Yusuke Yamamoto

    Department of Cardiac Surgery, Asahikawa Medical University, Asahikawa, Japan
    Competing interests
    The authors declare that no competing interests exist.

  5. Weilian Zhang

    Structural Genomics Consortium, University of Toronto, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.

  6. Aiping Dong

    Structural Genomics Consortium, University of Toronto, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.

  7. Yanjun Li

    Structural Genomics Consortium, University of Toronto, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.

  8. Yuriko Yoshimura

    Division of Chromatin Regulation, National Institute for Basic Biology, Okazaki, Japan
    Competing interests
    The authors declare that no competing interests exist.

  9. Hiroyuki Kamiya

    Department of Cardiac Surgery, Asahikawa Medical University, Asahikawa, Japan
    Competing interests
    The authors declare that no competing interests exist.

  10. Jun-ichi Nakayama

    Division of Chromatin Regulation, National Institute of Basic Biology, Okazaki, Japan
    Competing interests
    The authors declare that no competing interests exist.

  11. Jun Ueda

    Centre for Advanced Research and Education, Asahikawa Medical University, Asahikawa, Japan
    Competing interests
    The authors declare that no competing interests exist.

  12. Jinrong Min

    Structural Genomics Consortium, University of Toronto, Toronto, Canada
    For correspondence
    jr.min@utoronto.ca
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5210-3130

Funding

National Natural Science Foundation of China (31900865)

  • Cheng Dong

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Xiaobing Shi, Van Andel Institute, United States

Publication history

  1. Received: May 8, 2020
  2. Accepted: August 29, 2020
  3. Accepted Manuscript published: September 1, 2020 (version 1)
  4. Accepted Manuscript updated: September 2, 2020 (version 2)
  5. Version of Record published: September 15, 2020 (version 3)

Copyright

© 2020, Dong et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 1,187
    Page views
  • 183
    Downloads
  • 5
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Categories and tags

Research organism

Further reading

    1. Structural Biology and Molecular Biophysics

    N501Y mutation of spike protein in SARS-CoV-2 strengthens its binding to receptor ACE2

    Fang Tian et al.
    Research Article Updated

    SARS-CoV-2 has been spreading around the world for the past year. Recently, several variants such as B.1.1.7 (alpha), B.1.351 (beta), and P.1 (gamma), which share a key mutation N501Y on the receptor-binding domain (RBD), appear to be more infectious to humans. To understand the underlying mechanism, we used a cell surface-binding assay, a kinetics study, a single-molecule technique, and a computational method to investigate the interaction between these RBD (mutations) and ACE2. Remarkably, RBD with the N501Y mutation exhibited a considerably stronger interaction, with a faster association rate and a slower dissociation rate. Atomic force microscopy (AFM)-based single-molecule force microscopy (SMFS) consistently quantified the interaction strength of RBD with the mutation as having increased binding probability and requiring increased unbinding force. Molecular dynamics simulations of RBD–ACE2 complexes indicated that the N501Y mutation introduced additional π-π and π-cation interactions that could explain the changes observed by force microscopy. Taken together, these results suggest that the reinforced RBD–ACE2 interaction that results from the N501Y mutation in the RBD should play an essential role in the higher rate of transmission of SARS-CoV-2 variants, and that future mutations in the RBD of the virus should be under surveillance.

    1. Microbiology and Infectious Disease
    2. Structural Biology and Molecular Biophysics

    Structural characterization of NrnC identifies unifying features of dinucleotidases

    Justin D Lormand et al.
    Research Advance

    RNA degradation is fundamental for cellular homeostasis. The process is carried out by various classes of endolytic and exolytic enzymes that together degrade an RNA polymer to mono-ribonucleotides. Within the exoribonucleases, nano-RNases play a unique role as they act on the smallest breakdown products and hence catalyze the final steps in the process. We recently showed that oligoribonuclease (Orn) acts as a dedicated diribonucleotidase, defining the ultimate step in RNA degradation that is crucial for cellular fitness (Kim et al., 2019). Whether such a specific activity exists in organisms that lack Orn-type exoribonucleases remained unclear. Through quantitative structure-function analyses we show here that NrnC-type RNases share this narrow substrate length preference with Orn. Although NrnC employs similar structural features that distinguish these two classes as dinucleotidases from other exonucleases, the key determinants for dinucleotidase activity are realized through distinct structural scaffolds. The structures together with comparative genomic analyses of the phylogeny of DEDD-type exoribonucleases indicates convergent evolution as the mechanism of how dinucleotidase activity emerged repeatedly in various organisms. The evolutionary pressure to maintain dinucleotidase activity further underlines the important role these analogous proteins play for cell growth.

    1. Structural Biology and Molecular Biophysics

    Regulation of human mTOR complexes by DEPTOR

    Matthias Wälchli et al.
    Research Article

    The vertebrate-specific DEP domain-containing mTOR interacting protein (DEPTOR), an oncoprotein or tumor suppressor, has important roles in metabolism, immunity, and cancer. It is the only protein that binds and regulates both complexes of mammalian target of rapamycin (mTOR), a central regulator of cell growth. Biochemical analysis and cryo-EM reconstructions of DEPTOR bound to human mTOR complex 1 (mTORC1) and mTORC2 reveal that both structured regions of DEPTOR, the PDZ domain and the DEP domain tandem (DEPt), are involved in mTOR interaction. The PDZ domain binds tightly with mildly activating effect, but then acts as an anchor for DEPt association that allosterically suppresses mTOR activation. The binding interfaces of the PDZ domain and DEPt also support further regulation by other signaling pathways. A separate, substrate-like mode of interaction for DEPTOR phosphorylation by mTOR complexes rationalizes inhibition of non-stimulated mTOR activity at higher DEPTOR concentrations. The multifaceted interplay between DEPTOR and mTOR provides a basis for understanding the divergent roles of DEPTOR in physiology and opens new routes for targeting the mTOR-DEPTOR interaction in disease.