Biology subjects

Galstyan, V.

Publications and source records attributed to Galstyan, V..

7 recordsLinked to original sources

bioRxiv2024

With the leisure of time, kinetic proofreading does reliable ligand discrimination after all

In a recent PNAS publication, Kirby and Zilman studied kinetic proofreading for receptor signaling and argued that having more proofreading steps does not generally improve ligand discrimination when stochastic effects are taken into account. In their analysis, however, the authors made an implicit assumption about a fixed discrimination time, which is not always warranted. We show that when the discrimination time is allowed to vary in order to maintain a fixed level of signaling activity, the proofreading performance can, in fact, uniformly improve with the number of steps. We therefore call for a comprehensive study of the interplay between discrimination time, discrimination accuracy, and signaling activity, where the two seemingly contradictory results will be slices of the trade-off surface along different axes.

systems biology↗

bioRxiv2023

Trade-offs between cost and information in cellular prediction

Living cells can leverage correlations in environmental fluctuations to predict the future environment and mount a response ahead of time. To this end, cells need to encode the past signal into the output of the intracellular network from which the future input is predicted. Yet, storing information is costly while not all features of the past signal are equally informative on the future input signal. Here, we show, for two classes of input signals, that cellular networks can reach the fundamental bound on the predictive information as set by the information extracted from the past signal: pushpull networks can reach this information bound for Markovian signals, while networks that take a temporal derivative can reach the bound for predicting the future derivative of non-Markovian signals. However, the bits of past information that are most informative about the future signal are also prohibitively costly. As a result, the optimal system that maximizes the predictive information for a given resource cost is, in general, not at the information bound. Applying our theory to the chemotaxis network of Escherichia coli reveals that its adaptive kernel is optimal for predicting future concentration changes over a broad range of background concentrations, and that the system has been tailored to predicting these changes in shallow gradients.

biophysics↗

bioRxiv2022

Modeling and mechanical perturbations reveal how spatially regulated anchorage gives rise to spatially distinct mechanics across the mammalian spindle

During cell division, the spindle generates force to move chromosomes. In mammals, microtubule bundles called kinetochore-fibers (k-fibers) attach to and segregate chromosomes. To do so, k-fibers must be robustly anchored to the dynamic spindle. We previously developed microneedle manipulation to mechanically challenge k-fiber anchorage, and observed spatially distinct response features revealing the presence of heterogeneous anchorage (Suresh et al. 2020). How anchorage is precisely spatially regulated, and what forces are necessary and sufficient to recapitulate the k-fibers response to force remain unclear. Here, we develop a coarse-grained k-fiber model and combine with manipulation experiments to infer underlying anchorage using shape analysis. By systematically testing different anchorage schemes, we find that forces solely at k-fiber ends are sufficient to recapitulate unmanipulated k-fiber shapes, but not manipulated ones for which lateral anchorage over a 3 m length scale near chromosomes is also essential. Such anchorage robustly preserves k-fiber orientation near chromosomes while allowing pivoting around poles. Anchorage over a shorter length scale cannot robustly restrict pivoting near chromosomes, while anchorage throughout the spindle obstructs pivoting at poles. Together, this work reveals how spatially regulated anchorage gives rise to spatially distinct mechanics in the mammalian spindle, which we propose are key for function.

biophysics↗

bioRxiv2021

Motor processivity and speed determine structure and dynamics of microtubule-motor assemblies

1Active matter systems can generate highly ordered structures, avoiding equilibrium through the consumption of energy by individual constituents. How the microscopic parameters that characterize the active agents are translated to the observed mesoscopic properties of the assembly has remained an open question. These active systems are prevalent in living matter; for example, in cells, the cytoskeleton is organized into structures such as the mitotic spindle through the coordinated activity of many motor proteins walking along microtubules. Here, we investigate how the microscopic motor-microtubule interactions affect the coherent structures formed in a reconstituted motor-microtubule system. This question is of deeper evolutionary significance as we suspect motor and microtubule type contribute to the shape and size of resulting structures. We explore key parameters experimentally and theoretically, using a variety of motors with different speeds, proces-sivities, and directionalities. We demonstrate that aster size depends on the motor used to create the aster, and develop a model for the distribution of motors and microtubules in steady-state asters that depends on parameters related to motor speed and processivity. Further, we show that network contraction rates scale linearly with the single-motor speed in quasi one-dimensional contraction experiments. In all, this theoretical and experimental work helps elucidate how microscopic motor properties are translated to the much larger scale of collective motor-microtubule assemblies.

biophysics↗

bioRxiv2020

Proofreading through spatial gradients

Key enzymatic processes in biology use the nonequilibrium error correction mechanism called kinetic proofreading to enhance their specificity. Kinetic proofreading typically requires several dedicated structural features in the enzyme, such as a nucleotide hydrolysis site and multiple enzyme-substrate conformations that delay product formation. Such requirements limit the applicability and the adaptability of traditional proofreading schemes. Here, we explore an alternative conceptual mechanism of error correction that achieves delays between substrate binding and subsequent product formation by having these events occur at distinct physical locations. The time taken by the enzyme-substrate complex to diffuse from one location to another is leveraged to discard wrong substrates. This mechanism does not require dedicated structural elements on the enzyme, making it easier to overlook in experiments but also making proofreading tunable on the fly. We discuss how tuning the length scales of enzyme or substrate concentration gradients changes the fidelity, speed and energy dissipation, and quantify the performance limitations imposed by realistic diffusion and reaction rates in the cell. Our work broadens the applicability of kinetic proofreading and sets the stage for the study of spatial gradients as a possible route to specificity.

biophysics↗

bioRxiv2018

Combinatorial Control through Allostery

Many instances of cellular signaling and transcriptional regulation involve switch-like molecular responses to the presence or absence of input ligands. To understand how these responses come about and how they can be harnessed, we develop a statistical mechanical model to characterize the types of Boolean logic that can arise from allosteric molecules following the Monod-Wyman-Changeux (MWC) model. Building upon previous work, we show how an allosteric molecule regulated by two inputs can elicit AND, OR, NAND and NOR responses, but is unable to realize XOR or XNOR gates. Next, we demonstrate the ability of an MWC molecule to perform ratiometric sensing - a response behavior where activity depends monotonically on the ratio of ligand concentrations. We then extend our analysis to more general schemes of combinatorial control involving either additional binding sites for the two ligands or an additional third ligand and show how these additions can cause a switch in the logic behavior of the molecule. Overall, our results demonstrate the wide variety of control schemes that biological systems can implement using simple mechanisms.

biophysics↗

bioRxiv2018

Binary transcriptional control of pattern formation in development

Predicting developmental outcomes from regulatory DNA sequence and transcription factor patterns remains an open challenge in physical biology. Using stripe 2 of the even-skipped gene in Drosophila embryos as a case study, we dissect the regulatory forces underpinning a key step along the developmental decision-making cascade: the generation of cytoplasmic mRNA patterns via the control of transcription in individual cells. Using live imaging and computational approaches, we found that the transcriptional burst frequency is modulated across the stripe to control the mRNA production rate. However, we discovered that bursting alone cannot quantitatively recapitulate the formation of the stripe, and that control of the window of time over which each nucleus transcribes even-skipped plays a critical role in stripe formation. Theoretical modeling revealed that these regulatory strategies--bursting and the time window--obey different kinds of regulatory logic, suggesting that the stripe is shaped by the interplay of two distinct underlying molecular processes.

developmental biology↗