Characterization of functional disordered regions within chromatin-associated proteins

Abstract

Summary Intrinsically disordered regions (IDRs) are abundant and play important roles in the function of chromatin-associated proteins (CAPs). These regions are often found at the N- and C-termini of CAPs and between structured domains, where they can act as more than just linkers, directly contributing to function. IDRs have been shown to contribute to substrate binding, act as auto-regulatory regions, and drive liquid-liquid droplet formation. Their disordered nature provides increased functional diversity and allows them to be easily regulated through post-translational modification. However, these regions can be especially challenging to characterize on a structural level. Here, we review the prevalence of IDRs in CAPs, highlighting several studies that address their importance in CAP function and show progress in structural characterization of these regions. A focus is placed on the unique opportunity to apply nuclear magnetic resonance (NMR) spectroscopy alongside cryo-electron microscopy to characterize IDRs in CAPs.

Histone acylations and chromatin dynamics: concepts, challenges, and links to metabolism

“…This loss of flexibility could additionally limit internucleosomal interactions (Collepardo-Guevara et al, 2015) and thus provide another perspective on how H4K16ac opens up chromatin. This insight was based on nuclear magnetic resonance (NMR) spectroscopy, which enables analysis of nucleosome structure and tail dynamics in combination with computational simulation studies (Musselman & Kutateladze, 2021). Similar approaches could be used to systematically compare the effect of non-acetyl acylations on histone tail dynamics for all core Box 1: Histone modification mimics and designer chromatin Site-specific mutations of histones have been used to mimic modifications or the unmodified state.…”

ProMetheusDB: an in-depth analysis of the high-quality human methyl-proteome

“…In the last two decades, intrinsically disordered regions (IDRs) of proteins have been reported to play a role in different processes (such as protein:protein and protein:nucleic acid interactions and protein phase separation) and often be modified by PTMs, including R methylation (Bremang et al, 2013; Darling & Uversky, 2018; Musselman & Kutateladze, 2021). In addition, methylated Rs can serve as docking sites for the recruitment of other proteins and the formation of multi-protein complexes; two examples of R methylation “readers” are represented by the Tudor domain, found in several proteins linked to transcriptional regulation, mRNA splicing and formation of RNP granules (Ying & Chen, 2012), and the WD40 repeat domain, located on a wide range of scaffolding proteins whose role is to bring together interactions partners into stable complexes (Jain & Pandey, 2018).…”

Dimerization Activity of a Disordered N-Terminal Domain from Drosophila CLAMP Protein

“…In comparison with CTCF, the N-terminal domain of CLAMP apparently has more dynamic folding, which is reflected by SAXS and NMR data more typical of IDRs. Intrinsically disordered proteins are abundant within the structures of transcription factors and other chromatin-associated proteins [ 15 , 18 ]. IDRs’ protein–protein interaction properties are difficult to predict [ 56 ], and thus similar domains could be widespread within eukaryotic transcription factors.…”

“…This domain lacks secondary structure and has biochemical properties more typical of an intrinsically disordered region (IDR) [ 12 ]. IDRs are abundant in chromatin-associated proteins [ 15 , 16 ], playing diverse roles in molecular recognition, chromatin compaction, and subcellular compartmentalization through phase separation [ 17 , 18 ].…”