An aromatic cage is required but not sufficient for binding of Tudor domains of the Polycomblike protein family to H3K36me3

Gatchalian, Jovylyn; Kingsley, Molly C.; Moslet, Stacey D; Ospina, Ruben D Rosas; Kutateladze, Tatiana G.

doi:10.1080/15592294.2015.1042646

Cited by 15 publications

(19 citation statements)

References 28 publications

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“…Interestingly, the binding affinity of MTF2 to an H3K36me3 peptide is much lower than that of PHF1 due to loss of a key aromatic residue ( Fig. 5A; Gatchalian et al 2015;Li et al 2017). Thus, while all PCLs stimulate PRC2 activity, we speculate that MTF2 mediates PRC2 recruitment to sites devoid of H3K36me2/me3, while PHF1 and PHF19 stabilize PRC2 on sites occupied by H3K36me2/me3.…”

Section: Features Of the Prc2 Holoenzyme Regulated By Distinct Accessmentioning

confidence: 88%

PRC2 is high maintenance

et al. 2019

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As the process that silences gene expression ensues during development, the stage is set for the activity of Polycomb-repressive complex 2 (PRC2) to maintain these repressed gene profiles. PRC2 catalyzes a specific histone posttranslational modification (hPTM) that fosters chromatin compaction. PRC2 also facilitates the inheritance of this hPTM through its self-contained “write and read” activities, key to preserving cellular identity during cell division. As these changes in gene expression occur without changes in DNA sequence and are inherited, the process is epigenetic in scope. Mutants of mammalian PRC2 or of its histone substrate contribute to the cancer process and other diseases, and research into these aberrant pathways is yielding viable candidates for therapeutic targeting. The effectiveness of PRC2 hinges on its being recruited to the proper chromatin sites; however, resolving the determinants to this process in the mammalian case was not straightforward and thus piqued the interest of many in the field. Here, we chronicle the latest advances toward exposing mammalian PRC2 and its high maintenance.

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Section: Features Of the Prc2 Holoenzyme Regulated By Distinct Accessmentioning

confidence: 88%

PRC2 is high maintenance

et al. 2019

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“…Ser86 in MTF2 takes the place of an aromatic residue, which is Phe71 in PHF1 or Tyr80 in PHF19, respectively ( Figure 1G). This incomplete aromatic cage might cause the weaker binding ability of H3tK27me3, like that of H3K36me3 (Gatchalian et al, 2015). Indeed, mutating Ser86 of MTF2 to phenylalanine or tyrosine resulted in dramatically enhanced binding affinities (Table 1).…”

Section: Tudor Domains Of Phf1 and Phf19 Preferentially Bind To Testimentioning

confidence: 99%

Structural basis for histone variant H3tK27me3 recognition by PHF1 and PHF19

Cheng

Nakagawa

Oyama

et al. 2020

eLife

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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.

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“…We have previously shown that the complete aromatic cage in the Tudor domain of Drosophila Pcl is necessary but insufficient for binding to H3K36me3 and that the adjacent hydrophobic patch is also required 26 . The fact that we were unable to generate the gain-of-function mutant of Set4 by engineering the Set3-like aromatic cage suggests that other surface residues play an imperative role.…”

Section: Resultsmentioning

confidence: 99%

Structural Insight into Recognition of Methylated Histone H3K4 by Set3

Gatchalian

Ali

Andrews

et al. 2017

Journal of Molecular Biology

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The plant homeodomain (PHD) finger of Set3 binds methylated lysine 4 of histone H3 in vitro and in vivo, however precise selectivity of this domain has not been fully characterized. Here, we explore the determinants of methyllysine recognition by the PHD fingers of Set3 and its orthologs. We use X-ray crystallographic and spectroscopic approaches to show that the Set3 PHD finger binds di- and trimethylated states of H3K4 with comparable affinities and employs similar molecular mechanisms to form complexes with either mark. Composition of the methyllysine-binding pocket plays an essential role in determining the selectivity of the PHD fingers. The finding that the histone-binding activity is not conserved in the PHD finger of Set4 suggests different functions for the Set3 and Set4 paralogs.

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An aromatic cage is required but not sufficient for binding of Tudor domains of the Polycomblike protein family to H3K36me3

Cited by 15 publications

References 28 publications

PRC2 is high maintenance

PRC2 is high maintenance

Structural basis for histone variant H3tK27me3 recognition by PHF1 and PHF19

Structural Insight into Recognition of Methylated Histone H3K4 by Set3

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