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Liberalism’s betrayal of itself—and the way back

By www.chathamhouse.org
Published On :: Mon, 10 Feb 2020 16:19:11 +0000

Source

The Economist

Release date

14 February 2019

Expert

Hans Kundnani

In the news type

Op-ed

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Assad’s extortion fails to ease Syria’s financial crisis

By www.chathamhouse.org
Published On :: Mon, 24 Feb 2020 14:55:32 +0000

Source

Arab News

URL

https://www.arabnews.com/node/1625786

Release date

10 February 2020

Expert

Haid Haid

In the news type

Op-ed

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Regional politics of Kazakhstan in Central Asia

By www.chathamhouse.org
Published On :: Wed, 06 May 2020 17:21:20 +0000

Source

Central Asia Analytical Network

URL

https://caa-network.org/archives/18673

Release date

03 December 2019

Expert

Annette Bohr

In the news type

Op-ed

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Molecular basis for histone H3 “K4me3-K9me3/2” methylation pattern readout by Spindlin1 [Gene Regulation]

By www.jbc.org
Published On :: 2020-12-04T00:06:06-08:00

Histone recognition by “reader” modules serves as a fundamental mechanism in epigenetic regulation. Previous studies have shown that Spindlin1 is a reader of histone H3K4me3 as well as “K4me3-R8me2a” and promotes transcription of rDNA or Wnt/TCF4 target genes. Here we show that Spindlin1 also acts as a potent reader of histone H3 “K4me3-K9me3/2” bivalent methylation pattern. Calorimetric titration revealed a binding affinity of 16 nm between Spindlin1 and H3 “K4me3-K9me3” peptide, which is one to three orders of magnitude stronger than most other histone readout events at peptide level. Structural studies revealed concurrent recognition of H3K4me3 and H3K9me3/2 by aromatic pockets 2 and 1 of Spindlin1, respectively. Epigenomic profiling studies showed that Spindlin1 colocalizes with both H3K4me3 and H3K9me3 peaks in a subset of genes enriched in biological processes of transcription and its regulation. Moreover, the distribution of Spindlin1 peaks is primarily associated with H3K4me3 but not H3K9me3, which suggests that Spindlin1 is a downstream effector of H3K4me3 generated in heterochromatic regions. Collectively, our work calls attention to an intriguing function of Spindlin1 as a potent H3 “K4me3-K9me3/2” bivalent mark reader, thereby balancing gene expression and silencing in H3K9me3/2-enriched regions.


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Coupled intra- and interdomain dynamics support domain cross-talk in Pin1 [Signal Transduction]

By www.jbc.org
Published On :: 2020-12-04T00:06:05-08:00

The functional mechanisms of multidomain proteins often exploit interdomain interactions, or “cross-talk.” An example is human Pin1, an essential mitotic regulator consisting of a Trp–Trp (WW) domain flexibly tethered to a peptidyl-prolyl isomerase (PPIase) domain, resulting in interdomain interactions important for Pin1 function. Substrate binding to the WW domain alters its transient contacts with the PPIase domain via means that are only partially understood. Accordingly, we have investigated Pin1 interdomain interactions using NMR paramagnetic relaxation enhancement (PRE) and molecular dynamics (MD) simulations. The PREs show that apo-Pin1 samples interdomain contacts beyond the range suggested by previous structural studies. They further show that substrate binding to the WW domain simultaneously alters interdomain separation and the internal conformation of the WW domain. A 4.5-μs all-atom MD simulation of apo-Pin1 suggests that the fluctuations of interdomain distances are correlated with fluctuations of WW domain interresidue contacts involved in substrate binding. Thus, the interdomain/WW domain conformations sampled by apo-Pin1 may already include a range of conformations appropriate for binding Pin1's numerous substrates. The proposed coupling between intra-/interdomain conformational fluctuations is a consequence of the dynamic modular architecture of Pin1. Such modular architecture is common among cell-cycle proteins; thus, the WW–PPIase domain cross-talk mechanisms of Pin1 may be relevant for their mechanisms as well.


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