Regulation of RNA-binding proteins affinity to export receptors enables the nuclear basket proteins to distinguish and retain aberrant mRNAs

Abstract

Export of messenger ribonucleic acids (mRNAs) into the cytoplasm is a fundamental step in gene regulation processes, which is meticulously quality controlled by highly efficient mechanisms in eukaryotic cells. Yet, it remains unclear how the aberrant mRNAs are recognized and retained inside the nucleus. Using a new modelling approach for complex systems, namely the agent-based modelling (ABM) approach, we develop a minimal model of the mRNA quality control (QC) mechanism. Our results demonstrate that regulation of the affinity of RNA-binding proteins (RBPs) to export receptors along with the weak interaction between the nuclear basket protein (Mlp1 or Tpr) and RBPs are the minimum requirements to distinguish and retain aberrant mRNAs. Our results show that the affinity between Tpr and RBPs is optimized to maximize the retention of aberrant mRNAs. In addition, we demonstrate how the length of mRNA affects the QC process. Since longer mRNAs spend more time in the nuclear basket to form a compact conformation and initiate their export, nuclear basket proteins could more easily capture and retain them inside the nucleus.

Agent‐Based Modeling in Molecular Systems Biology

“…At the molecular scale, however, these algorithms do not necessarily represent the molecular species and their dynamics with enough accuracy. Therefore, the above mentioned direct transformations of biophysical and biochemical characteristics of molecules into ABM parameters, which are validated in several different studies, provide a solid platform to more accurately model molecular systems and pave the path for wide utility of ABM in molecular systems biology.…”

“…A comparison between the size of the system of interest and the timescales achievable by different molecular computational modeling techniques including molecular dynamics (MD), coarse‐grained MD, Brownian dynamics, agent‐based modeling . Examples of studies employing these approaches are provided as references.…”

“…ABM, as a complex systems approach, has the ability to predict how a molecular system behaves given the rules that govern the behavior of individual molecules. Soheilypour and Mofrad, for example, demonstrated how modulating the affinities between the components involved in mRNA quality control could substantially alter the outcome of the system, that is export versus retention of mRNAs.…”

“…The mRNA ABM was in agreement with the former observations, showing that the rate‐limiting step was associated with reconfiguration of mRNA to thread itself into the central channel of the NPC. Furthermore, we recently explored the mRNA quality control mechanism . Prior to export, mRNAs are quality controlled to ensure the production of appropriately functioning proteins in the cytoplasm .…”

“…For the sake of visual clarity, a small fraction of actual concentrations is shown. Not drawn to scale Reproduced under the terms and conditions of the Creative Commons Attribution license 4.0 . Copyright 2016, the authors, published by Springer Nature.…”