Ref HAL: hal-01939067_v1
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Résumé:

Proteins are the basis of cellular functions, yet key parameters regulating protein synthesis remain elusive. Understanding the fine mechanisms of this regulation is a major goal of molecular and systems biology, and this knowledge will support many “synthetic biological” applications. We have the ambitious goal of providing a comprehensive modeling framework of one of the last steps of protein synthesis, namely mRNA translation. In this presentation I will focus from a modeler’s point of view, on the role of translation initiation and how this step is mainly dictated by ribosome abundances, finite size effects and recycling. We propose an approach based on the standard exclusion process, prototypic lattice gas model. This mathematical framework considers long-range dynamical effects often neglected in standard translation models. The model is compared to experimental ribosome density data, which are well reproduced qualitatively and quantitatively. The proposed mathematical framework thus describes the origins of the well-known and yet not understood relation between transcript efficiency and its length. We also speculate on the role of transcript length in the competition for ribosomes among different mRNAs.

Ref HAL: hal-01103149_v1
DOI: 10.1007/978-3-319-10629-8_70
WoS: 000380446300070
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1 Citation
Résumé:

The traffic of molecular motors is often represented by means of Poissonian particles moving on a unidimensional track. However, biological ‘particles’ generally advance with complicated stepping cycles, passing through different biochemical and conformational states. In this contribution we review an extension of the typical exclusion process, the archetypical model of unidimensional transport; we explore it first from a theoretical point of view, and then we show how it has been possible to provide quantitative comparisons to experiments in the context of mRNA translation.

Ref HAL: hal-01063014_v1
PMID 25204752
Ref Arxiv: 1408.2945
DOI: 10.1088/1478-3975/11/5/056006
WoS: 000343670600021
Ref. & Cit.: NASA ADS
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22 Citations
Résumé:

In cells and in vitro assays the number of motor proteins involved in biological transport processes is far from being unlimited. The cytoskeletal binding sites are in contact with the same finite reservoir of motors (either the cytosol or the flow chamber) and hence compete for recruiting the available motors, potentially depleting the reservoir and affecting cytoskeletal transport. In this work we provide a theoretical framework to study, analytically and numerically, how motor density profiles and crowding along cytoskeletal filaments depend on the competition of motors for their binding sites. We propose two models in which finite processive motor proteins actively advance along cytoskeletal filaments and are continuously exchanged with the motor pool. We first look at homogeneous reservoirs and then examine the effects of free motor diffusion in the surrounding medium. We consider as a reference situation recent in vitro experimental setups of kinesin-8 motors binding and moving along microtubule filaments in a flow chamber. We investigate how the crowding of linear motor proteins moving on a filament can be regulated by the balance between supply (concentration of motor proteins in the flow chamber) and demand (total number of polymerised tubulin heterodimers). We present analytical results for the density profiles of bound motors, the reservoir depletion, and propose novel phase diagrams that present the formation of jams of motor proteins on the filament as a function of two tuneable experimental parameters: the motor protein concentration and the concentration of tubulins polymerized into cytoskeletal filaments. Extensive numerical simulations corroborate the analytical results for parameters in the experimental range and also address the effects of diffusion of motor proteins in the reservoir.

Commentaires: 31 pages, 10 figures

Ref HAL: hal-01061351_v1
PMID 25185553
Ref Arxiv: 1312.1911
DOI: 10.1016/j.bpj.2014.07.012
WoS: 000341275100018
Ref. & Cit.: NASA ADS
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14 Citations
Résumé:

Motor enzymes are remarkable molecular machines that use the energy derived from the hydrolysis of a nucleoside triphosphate to generate mechanical movement, achieved through different steps that constitute their kinetic cycle. These macromolecules, nowadays investigated with advanced experimental techniques to unveil their molecular mechanisms and the properties of their kinetic cycles, are implicated in many biological processes, ranging from biopolymerisation (e.g. RNA polymerases and ribosomes) to intracellular transport (motor proteins such as kinesins or dyneins). Although the kinetics of individual motors is well studied on both theoretical and experimental grounds, the repercussions of their stepping cycle on the collective dynamics still remains unclear. Advances in this direction will improve our comprehension of transport process in the natural intracellular medium, where processive motor enzymes might operate in crowded conditions. In this work, we therefore extend the current statistical kinetic analysis to study collective transport phenomena of motors in terms of lattice gas models belonging to the exclusion process class. Via numerical simulations, we show how to interpret and use the randomness calculated from single particle trajectories in crowded conditions. Importantly, we also show that time fluctuations and non-Poissonian behavior are intrinsically related to spatial correlations and the emergence of large, but finite, clusters of co-moving motors. The properties unveiled by our analysis have important biological implications on the collective transport characteristics of processive motor enzymes in crowded conditions.

Commentaires: 9 pages, 6 figures, 2 supplementary figures

Résumé:

I will introduce the concept of non-equilibrium steady state, then apply it to unidimensional transport models like the totally asymmetric simple exclusion process (TASEP). I will then explain some of its variants and their biological applications.

Ref HAL: hal-01939150_v1
Exporter : BibTex | endNote
Résumé:

The traffic of molecular motors is often represented by means of Poissonian particles moving on a unidimensional track. However, biological ‘particles’ generally advance with complicated stepping cycles, passing through different biochemical and conformational states. In this contribution we review an extension of the typical exclusion process, the archetypical model of unidimensional transport; we explore it first from a theoretical point of view, and then we show how it has been possible to provide quantitative comparisons to experiments in the context of mRNA translation.

Ref HAL: hal-01939133_v1
Exporter : BibTex | endNote
Résumé:

Gene expression regulation is central to all living systems both at the level of transcription and translation. After the transcription of an mRNA strand from the DNA, many macromolecular machines called ribosomes concurrently "read" and translate each transcript. Understanding the impact of ribosomal traffic and its regulation is key to unravel the determinants of translation efficiency and protein synthesis.We have developed a collective stochastic model to simulate the ribosome flux dynamics across the entire yeast translatome, and we have shown how our model can make accurate predictions of the correspondence between steady-state mRNA and protein levels for each gene. Moreover, the analysis predicted physiological parameters of the translation process that can be related to physical properties of the system (as the three-dimensional conformation of the mRNA) or the balance between supply and demand of resources (as ribosome abundances).