Compact Modeling of Allosteric Multisite Proteins: Application to a Cell Size Checkpoint

Enciso, Germán; Kellogg, Douglas R.; Vargas, Anielle de

doi:10.1371/journal.pcbi.1003443

Cited by 8 publications

(16 citation statements)

References 47 publications

(66 reference statements)

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“…Pkc1 undergoes gradual hyperphosphorylation during polar membrane growth that is dependent upon and proportional to growth, consistent with the idea that it is part of a mechanism that measures polar membrane growth (Anastasia et al, 2012). Growth-dependent signaling suggests a simple and broadly relevant mechanism for control of cell growth and size (McCusker and Kellogg, 2012;Enciso et al, 2014).…”

Section: Introductionsupporting

confidence: 71%

A conserved signaling network monitors delivery of sphingolipids to the plasma membrane in budding yeast

Clarke

Dephoure

Horecka

et al. 2017

Preprint

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In budding yeast, cell cycle progression and ribosome biogenesis are dependent upon plasma membrane growth, which ensures that events of cell growth are coordinated with each other and with the cell cycle. However, the signals that link the cell cycle and ribosome biogenesis to membrane growth are poorly understood. Here, we used proteome-wide mass spectrometry to systematically discover signals associated with membrane growth. The results suggest that membrane trafficking events required for membrane growth generate sphingolipid-dependent signals. A conserved signaling network plays an essential role in signaling by responding to delivery of sphingolipids to the plasma membrane. In addition, sphingolipid-dependent signals control phosphorylation of protein kinase C (Pkc1), which plays an essential role in the pathways that link the cell cycle and ribosome biogenesis to membrane growth. Together, these discoveries provide new clues to how growth-dependent signals control cell growth and the cell cycle.

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Section: Introductionsupporting

confidence: 71%

A conserved signaling network monitors delivery of sphingolipids to the plasma membrane in budding yeast

Clarke

Dephoure

Horecka

et al. 2017

Preprint

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show abstract

“…In the following sections we illustrate how our results apply on different models from systems biology. Allosteric phosphorylation processes [10], substrate-catalyst interactions [18] as well as nucleosome-mediated cooperativity [25] are investigated.…”

Section: Illustrations From Systems Biologymentioning

confidence: 99%

“…Let us consider the model proposed in [10] where the protein is either active (A) or inactive (I), and has N sites that can be phosphorylated. The transition rates are given in Fig.…”

Section: Allosteric Phosphorylation Processesmentioning

confidence: 99%

“…The number of phosphorylated sites at time t is described by a process N (t), so that the full process is given by a bivariate time-continuous Markov chain (N (t), W (t)). The authors of [9,27,10] opt for Markov chains of transition rates…”

Section: Allosteric Phosphorylation Processesmentioning

confidence: 99%

“…Usually this occurs when N is large, but the fact of having many phosphorylation sites is not sufficient to ensure ultrasensitivity, see [17] or [29]. Various processes like protein or enzyme sequestration [4,23] or allosteric mechanisms, see e.g., [30,9,23,10,8] are known to induce ultrasensitivity. Our approach considers stochastic kinetics based on birth and death processes modeling phosphorylation processes.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Ultrasensitivity and sharp threshold theorems for multisite systems

Dougoud¹,

Mazza²,

Vinckenbosch³

2017

J. Phys. A: Math. Theor.

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We study the ultrasensitivity of multisite binding processes where ligand molecules can bind to several binding sites, considering more particularly recent models involving complex chemical reactions in phosphorylation systems such as allosteric phosphorylation processes, or substrate-catalyst chain reactions and nucleosome mediated cooperativity. New statistics based formulas for the Hill coefficient and the effective Hill coefficient are provided and necessary conditions for a system to be ultrasensitive are exhibited. We first show that the ultrasensitivity of binding processes can be approached using sharp-threshold theorems which have been developed in applied probability theory and statistical mechanics for studying sharp threshold phenomena in reliability theory, random graph theory and percolation theory. We hence introduce influence functions and show that general results can be obtained for monotone measures. We then assume that the binding process is described by a density dependent birth and death process. We provide precise large deviation results for the steady state distribution of the process, and show that switch-like ultrasensitive responses are strongly related to the multi-stability of the associated dynamical system. Ultrasensitivity occurs if and only if the entropy of the dynamical system has more than one global minimum for some critical ligand concentration. In this case, the Hill coefficient is proportional to the number of binding sites, and the systems is highly ultrasensitive. We also discuss the interpretation of an extension I q of the effective Hill coefficient I 0.9 for which we recommend the computation of a broad range of values of q instead of just the standard one corresponding to the 10% to 90% variation in the dose-response. It is shown that this single choice can sometimes mislead the conclusion by not detecting ultrasensitivity. This new approach allows a better understanding of multisite ultrasensitive systems and provides new tools for the design of such systems.

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The effect of site-to-site variability in ultrasensitive dose responses

Enciso

Ryerson

2016

J. Math. Biol.

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In this paper we study the ultrasensitive behavior of multisite phosphorylation or ligand binding systems, under site-to-site variations in the modification rates. Using computational methods and mathematical analysis, we prove that the Hill coefficient reaches its maximum value when all sites are identical to each other. This is shown for a non-cooperative multisite system with arbitrary activation function as well as for the well known MWC model. We also show that the Hill coefficient of the dose response is locally robust to variations in individual modification rates. The results suggest that maximal ultrasensitivity is reached when sites are similar to each other but not necessarily identical, a conformation found in unstructured modification domains present in many experimental systems.

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Compact Modeling of Allosteric Multisite Proteins: Application to a Cell Size Checkpoint

Cited by 8 publications

References 47 publications

A conserved signaling network monitors delivery of sphingolipids to the plasma membrane in budding yeast

A conserved signaling network monitors delivery of sphingolipids to the plasma membrane in budding yeast

Ultrasensitivity and sharp threshold theorems for multisite systems

The effect of site-to-site variability in ultrasensitive dose responses

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