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Entropic effect of macromolecular crowding enhances binding between nucleosome clutches in heterochromatin, but not in euchromatin.

ABSTRACT: Sharp increase in macromolecular crowding induces abnormal chromatin compaction in the cell nucleus, suggesting its non-negligible impact on chromatin structure and function. However, the details of the crowding-induced chromatin compaction remain poorly understood. In this work, we present a computer simulation study on the entropic effect of macromolecular crowding on the interaction between chromatin structural units called nucleosome clutches. Nucleosome clutches were modeled by a chain of nucleosomes collapsed by harmonic restraints implicitly mimicking the nucleosome association mediated by histone tails and linker histones. The nucleosome density of the clutches was set close to either that of high-density heterochromatin or that of low-density euchromatin. The effective interactions between these nucleosome clutches were calculated in various crowding conditions, and it was found that the increase in the degree of macromolecular crowding induced attractive interaction between two clutches with high nucleosome density. Interestingly, the increased degree of macromolecular crowding did not induce any attraction between two clutches with low nucleosome density. Our results suggest that the entropic effect of macromolecular crowding can enhance binding between nucleosome clutches in heterochromatin, but not in euchromatin, as a result of the difference in nucleosome packing degrees.

SUBMITTER: Oh I

PROVIDER: S-EPMC5882907 | biostudies-other | 2018 Apr

REPOSITORIES: biostudies-other

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Entropic effect of macromolecular crowding enhances binding between nucleosome clutches in heterochromatin, but not in euchromatin.

Oh Inrok I Choi Saehyun S Jung YounJoon Y Kim Jun Soo JS

Scientific reports 20180403 1

Sharp increase in macromolecular crowding induces abnormal chromatin compaction in the cell nucleus, suggesting its non-negligible impact on chromatin structure and function. However, the details of the crowding-induced chromatin compaction remain poorly understood. In this work, we present a computer simulation study on the entropic effect of macromolecular crowding on the interaction between chromatin structural units called nucleosome clutches. Nucleosome clutches were modeled by a chain of n ...[more]

PMID: 29615710

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Project description:BackgroundAmyloid fibrils associated with neurodegenerative diseases can be considered biologically relevant failures of cellular quality control mechanisms. It is known that in vivo human Tau protein, human prion protein, and human copper, zinc superoxide dismutase (SOD1) have the tendency to form fibril deposits in a variety of tissues and they are associated with different neurodegenerative diseases, while rabbit prion protein and hen egg white lysozyme do not readily form fibrils and are unlikely to cause neurodegenerative diseases. In this study, we have investigated the contrasting effect of macromolecular crowding on fibril formation of different proteins.Methodology/principal findingsAs revealed by assays based on thioflavin T binding and turbidity, human Tau fragments, when phosphorylated by glycogen synthase kinase-3?, do not form filaments in the absence of a crowding agent but do form fibrils in the presence of a crowding agent, and the presence of a strong crowding agent dramatically promotes amyloid fibril formation of human prion protein and its two pathogenic mutants E196K and D178N. Such an enhancing effect of macromolecular crowding on fibril formation is also observed for a pathological human SOD1 mutant A4V. On the other hand, rabbit prion protein and hen lysozyme do not form amyloid fibrils when a crowding agent at 300 g/l is used but do form fibrils in the absence of a crowding agent. Furthermore, aggregation of these two proteins is remarkably inhibited by Ficoll 70 and dextran 70 at 200 g/l.Conclusions/significanceWe suggest that proteins associated with neurodegenerative diseases are more likely to form amyloid fibrils under crowded conditions than in dilute solutions. By contrast, some of the proteins that are not neurodegenerative disease-associated are unlikely to misfold in crowded physiological environments. A possible explanation for the contrasting effect of macromolecular crowding on these two sets of proteins (amyloidogenic proteins and non-amyloidogenic proteins) has been proposed.

Project description:Binding of the Ca2+/calmodulin(CaM)-dependent protein kinase II (CaMKII) to the NMDA-type glutamate receptor (NMDAR) subunit GluN2B controls long-term potentiation (LTP), a form of synaptic plasticity thought to underlie learning and memory. Regulation of this interaction is well-studied biochemically, but not under conditions that mimic the macromolecular crowding found within cells. Notably, previous molecular crowding experiments with lysozyme indicated an effect on the CaMKII holoenzyme conformation. Here, we found that the effect of molecular crowding on Ca2+/CaM-induced CaMKII binding to immobilized GluN2B in vitro depended on the specific crowding reagent. While binding was reduced by lysozyme, it was enhanced by BSA. The ATP content in the BSA preparation caused CaMKII autophosphorylation at T286 during the binding reaction; however, enhanced binding was also observed when autophosphorylation was blocked. Importantly, the positive regulation by nucleotide and BSA (as well as other macromolecular crowding reagents) did not alleviate the requirement for CaMKII stimulation to induce GluN2B binding. The differential effect of lysozyme (14 kDa) and BSA (66 kDa) was not due to size difference, as both dextran-10 and dextran-70 enhanced binding. By contrast, crowding with immunoglobulin G (IgG) reduced binding. Notably, lysozyme and IgG but not BSA directly bound to Ca2+/CaM in an overlay assay, suggesting a competition of lysozyme and IgG with the Ca2+/CaM-stimulus that induces CaMKII/GluN2B binding. However, lysozyme negatively regulated binding even when it was instead induced by CaMKII T286 phosphorylation. Alternative modes of competition would be with CaMKII or GluN2B, and the negative effects of lysozyme and IgG indeed also correlated with specific or non-specific binding to the immobilized GluN2B. Thus, the effect of any specific crowding reagent can differ, depending on its additional direct effects on CaMKII/GluN2B binding. However, the results of this study also indicate that, in principle, macromolecular crowding enhances CaMKII binding to GluN2B.

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Entropic effect of macromolecular crowding enhances binding between nucleosome clutches in heterochromatin, but not in euchromatin.

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Entropic effect of macromolecular crowding enhances binding between nucleosome clutches in heterochromatin, but not in euchromatin.

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