The Limiting-Pool Mechanism Fails to Control the Size of Multiple Organelles

Mohapatra, Lishibanya; Lagny, Thibaut J.; Harbage, David; Jelenković, Predrag R.; Kondev, Jané

doi:10.1016/j.cels.2017.04.011

Cited by 42 publications

(47 citation statements)

References 25 publications

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“…In the limiting pool model for M > 1, departure from size control of individual structures is manifested either as large anticorrelated size fluctuations (for identical growth rates), or the faster growing structure ends up incorporating all the subunits [11]. We therefore hypothesize that a negative feedback between size and the growth rate of individual structures might ensure robust size control.…”

Section: Model For Size Regulation Of Multiple Structures Grown From mentioning

confidence: 95%

“…Since organelle size is determined by the amount of available subunits in the cytoplasm, which in turn scales with cell size, the limiting pool model naturally captures the scaling of organelle size with cell size. However, the limiting pool fails to capture size regulation of multiple competing structures [10,11], due to the absence of an underlying mechanism for sensing individual structure size. Failure of the limiting pool mechanism in determining the size of multiple structures suggests addi- * shiladtb@andrew.cmu.edu tional feedback design principles for organelle growth control.…”

Section: Introductionmentioning

confidence: 99%

“…This indeterminacy manifests as large size fluctuations (Fig. S1) in a stochastic description [11], where building blocks can transfer between individual structures with no free energy cost. The underlying reason is that the limiting pool model does not provide a mechanism to sense the individual size of the structures.…”

Section: Introductionmentioning

confidence: 99%

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Size regulation of multiple organelles competing for a shared subunit pool

Banerjee

2020

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How cells regulate the size of intracellular structures and organelles, despite continuous turnover in their component parts, is a longstanding question. Recent experiments suggest that size control of many intracellular assemblies is achieved through the depletion of a limiting subunit pool in the cytoplasm. While the limiting pool model ensures organelle size scaling with cell size, it does not provide a mechanism for robust size control of multiple co-existing structures. Here we propose a kinetic theory for size regulation of multiple structures that are assembled from a shared pool of subunits. We demonstrate that a negative feedback between the growth rate and the size of individual structures underlies size regulation of a wide variety of intracellular assemblies, from cytoskeletal filaments to three-dimensional organelles such as centrosomes and the nucleus. We identify the feedback motifs for size control in these structures, based on known molecular interactions, and quantitatively compare our theory with available experimental data. Furthermore, we show that a positive feedback between structure size and growth rate can lead to bistable size distributions arising from autocatalytic growth. In the limit of high subunit concentration, autocatalytic growth of multiple structures leads to stochastic selection of a single structure, elucidating a mechanism for polarity establishment.

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Section: Model For Size Regulation Of Multiple Structures Grown From mentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

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Size regulation of multiple organelles competing for a shared subunit pool

Banerjee

2020

Preprint

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“…For example, in vitro experiments have demonstrated how the size of the mitotic spindle depends on the size of the compartment in which it self-assembles, consistent with a limiting pool mechanism for length control[11]. In the case of multiple structures all assembled from the same pool of components this mechanism can only control the total number of subunits in all the structures, but is incapable of controlling the size of each individual structure[12]. How cells create and maintain multiple filamentous structures, such as cilia in a multiciliate cell, is the key question that motivates this paper.…”

Section: Introductionmentioning

confidence: 99%

Control of filament length by a depolymerizing gradient

Datta

Harbage

Kondev

2020

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5Cells assemble microns-long filamentous structures from protein monomers that are nanometers 6 in size. These structures are often highly dynamic, yet in order for them to function properly, 7 cells maintain precise filament lengths. In this paper, we investigate length dependent 8 depolymerization as a mechanism of length control. This mechanism has been recently proposed 9 for flagellar length control in the single cell organisms Chlamydomonas and Giardia. Length 10 dependent depolymerization can arise from a concentration gradient of a depolymerizing protein, 11 such as kinesin-13 in Giardia, along the length of the flagellum. Two possible scenarios are 12 considered, that of a linear and an exponential gradient of depolymerizing proteins. We compute 13 analytically the probability distributions of filament lengths for both scenarios and show how 14 these distributions are controlled by key biochemical parameters through a dimensionless 15 number that we identify. In Chlamydomonas cells it has been well documented that the assembly 16 dynamics of its two flagella are coupled via a shared pool of molecular components, and so we 17 investigate the effect of a limiting monomer pool on the length distributions. Finally, we 18 compare our calculations to experiments. While the computed mean lengths are consistent with 19 observations, the noise is two orders of magnitude smaller than the observed length fluctuations. 20 21 I. Introduction 22All eukaryotic cells contain nanometer-sized proteins that polymerize to form filaments that are 23 hundreds of nanometers to tens of microns in length. These filaments often associate with other 24 proteins to form larger structures that perform critical roles in cell division, cell motility, and 25 intracellular transport. They are often highly dynamic, experiencing a high turnover rate of their 26 constitutive protein subunits [1,2]. Despite this, in order to function properly some of these 27 structures, like the mitotic spindle, or actin cables in budding yeast[2,3] must maintain specific 28 and well-defined sizes. 29When considering dynamics of filament length, the two basic processes are the addition of 30 monomer units, characterized by the rate of assembly, and the removal of these units, which is 31 described by the rate of disassembly. For the dynamics to reach a steady state with a well-32 defined length, one or both rates must be length dependent. Therefore, the search for the 33 molecular mechanism of length regulation often boils down to finding out whether the rate of 34 2 assembly or disassembly (or both) is length dependent, and what molecular-scale interactions 35 produce this length dependence [4,5]. 36 Many mechanisms for length regulation have been proposed based on careful experiments in 37 cells and on reconstituted filamentous structures in vitro[3,6-9]. One well studied mechanism 38 [10] of length control is to limit the number of subunits available for assembly. For example, in 39 vitro experiments have demonstrated how the size of the mitoti...

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“…This is a direct result of resource limitation and does not rely on the existence of a motor density gradient, as necessary for domain wall localization in the presence of unlimited resources [20][21][22][23]. So far, most work on the role of limited resources has focused on single components of the relevant system [17][18][19][24][25][26][27][28]. Only a few studies have considered simultaneous limitation of two resources [29].…”

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confidence: 99%

Limited Resources Induce Bistability in Microtubule Length Regulation

et al. 2018

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The availability of protein is an important factor for the determination of the size of the mitotic spindle. Involved in spindle-size regulation is kinesin-8, a molecular motor and microtubule (MT) depolymerase, which is known to tightly control MT length. Here, we propose and analyze a theoretical model in which kinesin-induced MT depolymerization competes with spontaneous polymerization while supplies of both tubulin and kinesin are limited. In contrast to previous studies where resources were unconstrained, we find that, for a wide range of concentrations, MT length regulation is bistable. We test our predictions by conducting in vitro experiments and find that the bistable behavior manifests in a bimodal MT length distribution. DOI: 10.1103/PhysRevLett.120.148101 The absolute and relative abundance of particular sets of proteins is important for a wide range of processes in cells. For example, during Xenopus laevis embryogenesis, importin α becomes progressively localized to the cell membrane [1]. As a consequence of importin's depletion from the cytoplasm, the protein kif2a escapes inactivation and decreases the size of the mitotic spindle. Similarly, formation of the mitotic spindle reduces the concentration of free tubulin dimers, the building blocks of microtubules (MTs). Thus, up to 60% of all tubulin heterodimers [2,3] may be incorporated into the spindle [4]. In addition, it has been shown in vivo and in vitro that both spindle size [4,5] and the lengths of its constituent MTs [6] scale with cytoplasmic volume.Assembly and disassembly of MTs are regulated by a set of proteins that interact with the plus ends of protofilaments [7,8]. One of these factors, the molecular motor kinesin-8, acts as a depolymerase [8,9]. As a consequence, spindle size increases in its absence [10] and decreases upon overexpression of the protein [11]. Moreover, the kinesin-8 homolog Kip3 from Saccharomyces cerevisiae has been shown to depolymerize MTs in a length-dependent fashion [9,12]. This is facilitated by a density gradient on the MT, caused by the interplay between the processive motion of Kip3 along the MT and its depolymerase activity at the plus end, which effectively enables the MT to "sense" its own length [12,13]. In combination with spontaneous MT polymerization, the Kip3 gradient leads to a length regulation mechanism [14,15].Here, we explore the combined effect of limited resources and Kip3-induced depolymerization on the length regulation of MTs. As seen in theoretical studies on the collective motion of molecular motors, resource limitation affects the density profile on the MT: regions of low and high motor density separate, as a localized domain wall emerges on the MT [16][17][18][19]. This is a direct result of resource limitation and does not rely on the existence of a motor density gradient, as necessary for domain wall localization in the presence of unlimited resources [20][21][22][23]. So far, most work on the role of limited resources has focused on single components of the relevant system [17][...

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The Limiting-Pool Mechanism Fails to Control the Size of Multiple Organelles

Cited by 42 publications

References 25 publications

Size regulation of multiple organelles competing for a shared subunit pool

Size regulation of multiple organelles competing for a shared subunit pool

Control of filament length by a depolymerizing gradient

Limited Resources Induce Bistability in Microtubule Length Regulation

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