Enhanced Nucleocytoplasmic Transport due to Competition for Elastic Binding Sites

Fogelson, Ben; Keener, James P.

doi:10.1016/j.bpj.2018.05.034

Cited by 18 publications

(52 citation statements)

References 60 publications

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“…Motion of multiple particles. In [3], we proposed a model for enhanced transport through the nuclear pore that relied on competition between two distinct species of particles for binding to a population of elastic tethers. Enhanced nuclear transport in that case depended on a set of biochemically motivated boundary conditions as well as the interaction between two distinct species of moving particles.…”

Section: Diffusion Mediated By Linearly-elastic Bindingmentioning

confidence: 99%

“…This situation is biologically relevant. It occurs in the nuclear pore complex in the interaction between karyopherin chaperones and elastic FG nucleoporins [3,8,9,13,15], and in a similar manner in the ciliary pore complex [6,12,17]. It is also relevant to the diffusion of signaling molecules near membranebound cognate receptors, where elasticity can come from the mechanical properties of the receptor or from the membrane itself.…”

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confidence: 99%

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Transport Facilitated by Rapid Binding to Elastic Tethers

Fogelson¹,

Keener²

2019

SIAM J. Appl. Math.

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Diffusion in cell biology is important and complicated. Diffusing particles must contend with a complex environment as they make their way through the cell. We analyze a particular type of complexity that arises when diffusing particles reversibly bind to elastically tethered binding partners. Using asymptotic analysis, we derive effective equations for the transport of both single and multiple particles in the presence of such elastic tethers. We show that for the case of linear elasticity and simple binding kinetics, the elastic tethers have a weak hindering effect on particle motion when only one particle is present, while, remarkably, strongly enhancing particle motion when multiple particles are present. We give a physical interpretation of this result that suggests a similar effect may be present in other biological settings.

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Section: Diffusion Mediated By Linearly-elastic Bindingmentioning

confidence: 99%

mentioning

confidence: 99%

Transport Facilitated by Rapid Binding to Elastic Tethers

Fogelson¹,

Keener²

2019

SIAM J. Appl. Math.

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“…Binding does not always enhance flux across a barrier. Mechanisms of selective transport include transport by mobile carriers and particle motion directly from one binding site to the next [18][19][20][21][22][23]. In general, selectivity requires that particles move while bound.…”

Section: Introductionmentioning

confidence: 99%

Design principles of selective transport through biopolymer barriers

Maguire

Stefferson

Betterton

et al. 2019

Preprint

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In biological systems, polymeric materials block the movement of some macromolecules while allowing the selective passage of others. In some cases, binding enables selective transport, while in others the most inert particles appear to transit most rapidly. To study the general principles of filtering, we develop a model motivated by features of the nuclear pore complex (NPC) which are highly conserved and could potentially be applied to other biological systems. The NPC allows selective transport of proteins called transport factors which transiently bind to disordered, flexible proteins called FG Nups. While the NPC is tuned for transport factors and their cargo, we show that a single feature is sufficient for selective transport: the bound-state motion resulting from transient binding to flexible filaments. Interchain transfer without unbinding can further improve selectivity, especially for crosslinked chains. We generalize this observation to model nanoparticle transport through mucus and show that bound-state motion accelerates transport of transient nanoparticle application, even with clearance by mucus flow. Our model provides a framework to control binding-induced selective transport in bipolymeric materials.

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“…Dynamic polymers allow a bound particle to move and may additionally drive motion due to elastic kicks when extended tethers bind ( Fig. 1B) (13,19,20). When applied to transport factors binding to disordered FG Nups within the NPC, a theory based on tethered diffusion agrees with experimental measurements of selective transport of NTF2 (4,13,21,22) suggesting that this mechanism may contribute to selective transport through the nuclear pore complex.…”

Section: Introductionmentioning

confidence: 62%

“…While previous work has shown that bound diffusion can lead to selective filtration (16)(17)(18), the molecular mechanisms that contribute to bound mobility and their relative importance remain poorly understood (13,19). We focus on determining whether binding to flexible tethers can lead to appreciable bound motion.…”

Section: Resultsmentioning

confidence: 99%

Bound-state diffusion due to binding to flexible polymers in a selective biofilter

Hough

Betterton

Maguire

2019

Preprint

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Selective biofilters are used by cells to control the transport of proteins, nucleic acids, and other macromolecules. Biological filters demonstrate both high specificity and rapid motion or high flux of proteins. In contrast, high flux comes at the expense of selectivity in many synthetic filters. Binding can lead to selective transport in systems in which the bound particle can diffuse, but the mechanisms that lead to bound diffusion remain unclear. Previous theory has proposed a molecular mechanism of bound-state mobility based only on transient binding to flexible polymers. However, this mechanism has not been directly tested in experiments. We demonstrate that bound mobility via tethered diffusion can be engineered into a synthetic gel using protein fragments derived from the nuclear pore complex. The resulting bound-state diffusion is quantitatively consistent with theory. Our results suggest that synthetic biological filters can be designed to to take advantage of tethered diffusion to give rapid, selective transport. SIGNIFICANCE Biological filters control the passage of proteins and other macromolecules between compartments of living systems. Determination of molecular mechanisms giving selective transport would enable the design of both selective filters and particles designed to penetrate biological barriers for drug delivery. One such mechanism arises from transient binding to dynamic polymer tethers. We designed a biomaterial which supports this type of tethered diffusion, demonstrating the potential to engineer bio-inspired filters.

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Enhanced Nucleocytoplasmic Transport due to Competition for Elastic Binding Sites

Cited by 18 publications

References 60 publications

Transport Facilitated by Rapid Binding to Elastic Tethers

Transport Facilitated by Rapid Binding to Elastic Tethers

Design principles of selective transport through biopolymer barriers

Bound-state diffusion due to binding to flexible polymers in a selective biofilter

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