Active Polycomb Repressive
Complex 2
Billy O'Neill '18 & Johnathan Cooper '19
Contents:
I. Introduction
Polycomb Repressive Complex 2 (PRC2) is one of the main
polycomb-group (PcG) complexes. Together with PRC1, these PcG
complexes are key epigenetic regulators of cell identity determination
and maintenance2. Specifically, PRC2 mediates the
methylation of histone H3 at lysine 27 -- a process that is indicative
of heterochromatin formation and subsequent gene silencing.
PRC2 is composed of 3 core subunits1:
enhancer of zeste 2 (Ezh2)
, embryonic ectoderm
development (Eed)
, and suppressor of zeste
12 (Suz12)
.
Improperly functioning PRC2 is linked to human diseases, including
numerous cancers, Weaver syndrome, and childhood glioblastoma1,3,4.
II. The Regulatory Moiety1
The regulatory moiety of Ezh2
is composed of six discrete domains that form a belt-like structure
which surrounds the Eed
subunit.
and
Initial contact by
Ezh2 on
Eed
is made by four regulatory sub-domains of
Ezh2
--
EBD, BAM,
SBD, and
SANT1L -- contact the
WD40
domain of
Eed.
Helix-and-loop regions of
EBD
are contacted by 7-bladed beta-propellor
WD40
domain of
Eed
Three beta-strands of
BAM
associate with the first and seventh blade of the beta-propellor,
tightening the connection between
Ezh2
and
Eed.
SBD
and
SANT1L form a
, and touch
Eed,
tightening the belt-like regulatory moiety of
Ezh2
around
Eed. Bulky aromatic
and hydrophobic residues in the alpha-helix bundle of the binary complex
stabilize
Eed.
III. The Catalytic Moiety1
The catalytic moiety of Ezh2
is composed of four discrete domains.
The substrate binding pocket
and cofactor-binding site
are located within the SET-I
and post-SET regions
respectively.
When PRC2 is in its basal site, the substrate
binding pocket is inaccessible and the cofactor-binding
pocket is incomplete. During activation, the SET-I
region rotates over twenty degrees counterclockwise. This exposes the
peptide substrate binding site
and results in the completion of the cofactor-binding
pocket, with the post-SET
region now primed for cofactor SAH binding.
The SET activation loop
SAL from the N-terminal
portion of Ezh2 sequence
extends from the Eed
surface toward the SET
domain and exits the catalytic moiety along the side of the last
beta-strand of SET-N.
Suz12(VEFS)
is located in the space behind the catalytic moiety of Ezh2.
The N-terminal loop region of Suz12(VEFS)
associates Eed with the
SAL and SET
regions of Ezh2.
The Suz12(VEFS)
subunit is bound to Ezh2
by regulatory sub-domains MCSS
and SANT2L that
form a ten-helix bundle with helical contents of Suz12(VEFS).
IV. PRC2 Function
The methylation of N terminus histone tails by methyltransferases is
associated with the formation of compact chromatin and, therefore,
transcription inhibition. Specifically, targets for methyltransferase
activity on histone 3 (H3) are a number of lysine residues -- K4, K9,
K27, and K36. PRC2 and its enzymatic subunit, Ezh2,
specifically target K27 on H32.
Silenced Versus Active Chromatin2
The chatacteristic SET
domain of Ezh2 functions
as a histone-lysine N-methyltransferase -- inducing the formation of
di- and tri- methylated lysine 27 (H3K27me)3.
This methylation induces compact or silent chromatin. The chromodomain
protein CDYL binds H3K27me marks (created by PRC2) and bridges PRC2 to
the chromatin. This interaction mediates PRC2 methytransferase activity
and creates a positive feedback loop to maintain the silent state on
chromatin
4. Additionally, H3K27me marks created by PRC2 can
be recognized by subunits of the PRC1 complex
2. This
recognition again promotes more chromatin silencing as recruitment of
PRC1 results in methylation of another H3 lysine — H3K9
2.
Inhibition by PRC22
PRC2’s role in large scale transcriptional regulation has
implications when it comes to proliferation and differentiation of
stem cells. Depending on PRC2 recruitment and the subsequent spread of
the silent state of chromatin, whole gene lineages can be made
accessible or inaccessible to transcriptional machinery.
PRC2 and Cell Differentiation2
V. References
1Jiao, L., & Liu, X. (2015). Structural basis of
histone H3K27 trimethylation by an active polycomb repressive complex
2. Science, 350(6258). doi:10.1126/science.aac4383
2Croce, L. D., & Helin, K. (2013). Transcriptional
regulation by Polycomb group proteins. Nature Structural &
Molecular Biology, 20(10), 1147-1155. doi:10.1038/nsmb.2669
3Yoo, K. H., & Hennighausen, L. (2012). EZH2
Methyltransferase and H3K27 Methylation in Breast Cancer.
International Journal of Biological Sciences, 8(1), 59-65.
doi:10.7150/ijbs.8.59
4Nichol, J.N.; Dupéré-Richer, D.; Ezponda, T.; Licht,
J.D.; Miller, W.H. (2016). H3K27 Mehtylation: A Focal Point of
Epigenetic Deregulation in Cancer. Advances in Cancer Research (131),
59-65.
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