Biology subjects

Dao Duc, K.

Publications and source records attributed to Dao Duc, K..

5 recordsLinked to original sources

bioRxiv2018

The key parameters that govern translation efficiency

Translation of mRNA into protein is a fundamental yet complex biological process with multiple factors that can potentially affect its efficiency. In particular, different genes can have quite different initiation rates, while site-specific elongation rates can vary substantially along a given transcript. Here, we analyze a stochastic model of translation dynamics to identify the key parameters that govern the overall rate of protein synthesis and the efficiency of ribosome usage. The mathematical model we study is an interacting particle system that generalizes the Totally Asymmetric Simple Exclusion Process (TASEP), where particles correspond to ribosomes. While the TASEP and its variants have been studied for the past several decades through simulations and mean field approximations, a general analytic solution has remained challenging to obtain. By analyzing the so-called hydrodynamic limit, we here obtain exact closed-form expressions for stationary currents and particle densities that agree well with Monte Carlo simulations. In addition, we provide a complete characterization of phase transitions in the system. Surprisingly, phase boundaries depend on only four parameters: the particle size, and the first, last and minimum particle jump rates. Relating these theoretical results to translation, we formulate four design principles that detail how to tune these parameters to optimize translation efficiency in terms of protein production rate and resource usage. We then analyze ribosome profiling data of S. cerevisiae and demonstrate that its translation system is generally efficient, consistent with the design principles we found. We discuss implications of our findings on evolutionary constraints and codon usage bias.

genomics↗

bioRxiv2018

Differences in the path to exit the ribosome across the three domains of life

Recent advances in biological imaging have led to a surge of fine-resolution structures of the ribosome from diverse organisms. Comparing these structures, especially the exit tunnel, to characterize the key similarities and differences across species is essential for various important applications, such as designing antibiotic drugs and understanding the intricate details of translation dynamics. Here, we compile and compare 20 fine-resolution cryo-EM and X-ray crystallography structures of the ribosome recently obtained from all three domains of life (bacteria, archaea and eukarya). We first show that a hierarchical clustering of tunnel shapes closely reflects the species phylogeny. Then, by analyzing the ribosomal RNAs and proteins localized near the tunnel, we explain the observed geometric variations and show direct association between the conservations of the geometry, structure, and sequence. We find that the tunnel is more conserved in its upper part, from the polypeptide transferase center to the constriction site. In the lower part, tunnels are significantly narrower in eukaryotes than in bacteria, and we provide evidence for the existence of a second constriction site in eukaryotic tunnels. We also show that ribosomal RNA and protein sequences are more likely to be conserved closer to the tunnel, as is the presence of positively charged amino acids. Overall, our comparative analysis shows how the geometric and biophysical properties of the exit tunnel play an important role in ensuring proper transit of the nascent polypeptide chain, and may explain the differences observed in several co-translational processes across species.

biophysics↗

bioRxiv2018

Dynamics of ion fluxes between neurons, astrocytes and the extracellular space during neurotransmission

Ionic homeostasis in the brain involves redistribution of ionic fluxes in several cell types and compartments, including neurons, astrocytes and the extracellular space. How the major ionic activity-dependent fluxes of potassium and sodium are individually regulated remains difficult to dissociate and to track experimentally. We here review recent progress in modeling the ionic fluxes evoked by neuronal activity based on mass conservation. Excitability of neurons indeed relies on inward sodium and outward potassium fluxes during action potential firing. Recently, we have developed a tri-compartment model based on mass-action kinetics equations that account for potassium dynamics between neurons, astrocytes and the extracellular space. This review describes how such type of model can be used to spatially and temporally predict potassium fluxes during various regimes of neuronal activity. In particular, the model initially showed that it takes several seconds for astrocytes to buffer the majority of the potassium rapidly released by neurons in both basal and high regime of activity. Such model can also probe the selective contribution of ionic channels, and revealed for instance that disruption of the main astroglial potassium Kir4.1 channels not only favors the emergence of epileptiform activity, but also dysregulates neuronal excitability specifically during slow rhythmic activities. We here also extend the predictions of the model by assessing the selective contribution of the astroglial and neuronal Na/K ATPase, or volume of the extracellular space on potassium dynamics. We discuss these findings and their implications for neuronal information processing in the healthy and diseased brain.

neuroscience↗

bioRxiv2017

Theoretical quantification of interference in the TASEP: Application to mRNA translation shows near-optimality of termination rates

The Totally Asymmetric Exclusion Process (TASEP) is a classical stochastic model for describing the transport of interacting particles, such as ribosomes moving along the mRNA during translation. Although this model has been widely studied in the past, the extent of collision between particles and the average distance between a particle to its nearest neighbor have not been quantified explicitly. We provide here a theoretical analysis of such quantities via the distribution of isolated particles. In the classical form of the model in which each particle occupies only a single site, we obtain an exact analytic solution using the Matrix Ansatz. We then employ a refined mean field approach to extend the analysis to a generalized TASEP with particles of an arbitrary size. Our theoretical study has direct applications in mRNA translation and the interpretation of experimental ribosome profiling data. In particular, our analysis of data from S. cerevisiae suggests a potential bias against the detection of nearby ribosomes with gap distance less than ~ 3 codons, which leads to some ambiguity in estimating the initiation rate and protein production flux for a substantial fraction of genes. Despite such ambiguity, however, we demonstrate theoretically that the interference rate associated with collisions can be robustly estimated, and show that approximately 1% of the translating ribosomes get obstructed.

systems biology↗

bioRxiv2016

Identification and quantitative analysis of the major determinants of translation elongation rate variation

Previous studies have shown that translation elongation is regulated by multiple factors, but the observed heterogeneity remains only partially explained. To dissect quantitatively the different determinants of elongation speed, we use probabilistic modeling to estimate initiation and local elongation rates from ribosome profiling data. This model-based approach allows us to quantify the extent of interference between ribosomes on the same transcript. We show that neither interference nor the distribution of slow codons is sufficient to explain the observed heterogeneity. Instead, we find that electrostatic interactions between the ribosomal exit tunnel and specific parts of the nascent polypeptide govern the elongation rate variation as the polypeptide makes its initial pass through the tunnel. Once the N-terminus has escaped the tunnel, the hydropathy of the nascent polypeptide within the ribosome plays a major role in modulating the speed. We show that our results are consistent with the biophysical properties of the tunnel.

genomics↗