Design Principles of Length Control of Cytoskeletal Structures

Mohapatra, Lishibanya; Goode, Bruce L.; Jelenković, Predrag R.; Phillips, Rob; Kondev, Jané

doi:10.1146/annurev-biophys-070915-094206

Cited by 71 publications

(102 citation statements)

References 55 publications

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“…Our analysis describes the limitations associated with the limiting-pool mechanism and underlines the necessity for the cell to invest in additional mechanisms to control size. In fact, there are other length-sensing mechanisms that have been reported in the filament literature (Andrianantoandro and Pollard, 2006; Chesarone-Cataldo et al, 2011; Gardner et al, 2011; Marshall et al, 2005; Mohapatra et al, 2015, 2016; Varga et al, 2006). In these studies specific proteins have been identified as being critical to length-control, and found to either modulate the assembly or the disassembly rate of cytoskeletal filaments in a length dependent fashion (Mohapatra et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, this mechanism is unable to maintain multiple structures that have a well-defined size, which assemble from a common pool of subunits. Cells can get around this problem by using additional size-regulatory mechanisms (Mohapatra et al, 2016). Quantitative experiments that measure the size and assembly dynamics of intracellular structures, and how they vary with different parameters, like the total amount of the limiting subunit or the size of the chamber within which they are assembled, are needed to quantitatively define the role of the limiting-pool mechanism in regulating size.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, several actin and formin binding proteins have been shown to play an important role in controlling cable length (Chesarone-Cataldo et al, 2011; Mohapatra et al, 2015, 2016). …”

Section: Figurementioning

confidence: 99%

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

et al. 2017

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Summary How the size of micron-scale cellular structures like the mitotic spindle, cytoskeletal filaments, the nucleus, the nucleolus and other non-membrane bound organelles is controlled despite a constant turnover of their constituent parts is a central problem in biology. Experiments have implicated the limiting-pool mechanism: structures grow by stochastic addition of molecular subunits from a finite pool until the rates of subunit addition and removal are balanced, producing a structure of well-defined size. Here, we consider these dynamics when multiple filamentous structures are assembled stochastically from a shared pool of subunits. Using analytical calculations and computer simulations, we show that robust size control can be achieved when only one filament is assembled at a time. When multiple filaments compete for monomers, filament lengths exhibit large fluctuations. These results extend to three-dimensional structures and reveal the physical limitations of the limiting pool mechanism of size-control when multiple organelles are assembled from a shared pool of subunits.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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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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“…Several mechanisms have been proposed that add effective cooperativity to these one-dimensional structures through length-dependent arrival of specialized molecules that modify the dynamics [23]. A thermodynamic analysis of these systems raises additional challenges beyond those produced by the intrinsic cooperativity of higher-dimensional models, because the energetics of the underlying molecular motor transport and enzyme activity would also have to be explicitly accounted for.…”

Section: Discussionmentioning

confidence: 99%