Conformational Control of the Binding of the Transactivation Domain of the MLL Protein and c-Myb to the KIX Domain of CREB

The KIX domain of CBP is a transcriptional coactivator. Concomitant binding to the activation domain of proto-oncogene protein c-Myb and the transactivation domain of the trithorax group protein mixed lineage leukemia (MLL) transcription factor lead to the biologically active ternary MLL∶KIX∶c-Myb complex which plays a role in Pol II-mediated transcription. The binding of the activation domain of MLL to KIX enhances c-Myb binding. Here we carried out molecular dynamics (MD) simulations for the MLL∶KIX∶c-Myb ternary complex, its binary components and KIX with the goal of providing a mechanistic explanation for the experimental observations. The dynamic behavior revealed that the MLL binding site is allosterically coupled to the c-Myb binding site. MLL binding redistributes the conformational ensemble of KIX, leading to higher populations of states which favor c-Myb binding. The key element in the allosteric communication pathways is the KIX loop, which acts as a control mechanism to enhance subsequent binding events. We tested this conclusion by in silico mutations of loop residues in the KIX∶MLL complex and by comparing wild type and mutant dynamics through MD simulations. The loop assumed MLL binding conformation similar to that observed in the KIX∶c-Myb state which disfavors the allosteric network. The coupling with c-Myb binding site faded, abolishing the positive cooperativity observed in the presence of MLL. Our major conclusion is that by eliciting a loop-mediated allosteric switch between the different states following the binding events, transcriptional activation can be regulated. The KIX system presents an example how nature makes use of conformational control in higher level regulation of transcriptional activity and thus cellular events

Understanding How Microplastics Affect Marine Biota on the Cellular Level Is Important for Assessing Ecosystem Function: A Review

Plastic has become indispensable for human life. When plastic debris is discarded into waterways, these items can interact with organisms. Of particular concern are microscopic plastic particles (microplastics) which are subject to ingestion by several taxa. This review summarizes the results of cutting-edge research about the interactions between a range of aquatic species and microplastics, including effects on biota physiology and secondary ingestion. Uptake pathways via digestive or ventilatory systems are discussed, including (1) the physical penetration of microplastic particles into cellular structures, (2) leaching of chemical additives or adsorbed persistent organic pollutants (POPs), and (3) consequences of bacterial or viral microbiota contamination associated with microplastic ingestion. Following uptake, a number of individual-level effects have been observed, including reduction of feeding activities, reduced growth and reproduction through cellular modifications, and oxidative stress. Microplastic-associated effects on marine biota have become increasingly investigated with growing concerns regarding human health through trophic transfer. We argue that research on the cellular interactions with microplastics provide an understanding of their impact to the organisms’ fitness and, therefore, its ability to sustain their functional role in the ecosystem. The review summarizes information from 236 scientific publications. Of those, only 4.6% extrapolate their research of microplastic intake on individual species to the impact on ecosystem functioning. We emphasize the need for risk evaluation from organismal effects to an ecosystem level to effectively evaluate the effect of microplastic pollution on marine environments. Further studies are encouraged to investigate sublethal effects in the context of environmentally relevant microplastic pollution conditions