Hitching a Ride: Mechanics of Transport Initiation through Linker-Mediated Hitchhiking

Mogre, Saurabh S.; Christensen, Jenna R; Niman, Cassandra; Reck-Peterson, Samara L.; Koslover, Elena F.

doi:10.1016/j.bpj.2020.01.024

Cited by 21 publications

(29 citation statements)

References 60 publications

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“…Models with spatially localized finite reaction rates have previously been employed in quantifying the kinetics of multi-conformation DNA-binding proteins searching for their genomic target sites [ 51 ], and of vesicles encountering cytoskeletal filaments to initiate motor-driven transport [ 52 ]. For one-dimensional models of a tubular geometry, finite reaction rates can also be used as a simplification to account for the radial diffusion time required to find a target by a particle that approaches its axial position [ 53 ].…”

Section: Computing Mean and Variance Of First Passage Timesmentioning

confidence: 99%

Diffusive search and trajectories on tubular networks: a propagator approach

et al. 2021

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Several organelles in eukaryotic cells, including mitochondria and the endoplasmic reticulum, form interconnected tubule networks extending throughout the cell. These tubular networks host many biochemical pathways that rely on proteins diffusively searching through the network to encounter binding partners or localized target regions. Predicting the behavior of such pathways requires a quantitative understanding of how confinement to a reticulated structure modulates reaction kinetics. In this work, we develop both exact analytical methods to compute mean first passage times and efficient kinetic Monte Carlo algorithms to simulate trajectories of particles diffusing in a tubular network. Our approach leverages exact propagator functions for the distribution of transition times between network nodes and allows large simulation time steps determined by the network structure. The methodology is applied to both synthetic planar networks and organelle network structures, demonstrating key general features such as the heterogeneity of search times in different network regions and the functional advantage of broadly distributing target sites throughout the network. The proposed algorithms pave the way for future exploration of the interrelationship between tubular network structure and biomolecular reaction kinetics. Graphic Abstract

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Section: Computing Mean and Variance Of First Passage Timesmentioning

confidence: 99%

Diffusive search and trajectories on tubular networks: a propagator approach

et al. 2021

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“…While many tubular cell projections exhibit a similar width of 1 − 2 µ m, the length from the distal tip to the nearest nuclear region can vary widely. In fungal hyphae, the distance from the hyphal tip to the first nucleus can range from a few to tens of microns in length [26, 27]. Neuronal axon lengths can vary from hundreds of micrometers up to a meter long [34].…”

Section: Resultsmentioning

confidence: 99%

“…1a). We set R = 1 µ m, as appropriate for both neuronal axons [25] and fungal hyphae [26, 27]. The cargo is modeled as a diffusive particle that either enters the cell at the distal tip, or starts uniformly distributed throughout the cell.…”

Section: Methodsmentioning

confidence: 99%

Optimizing microtubule arrangements for rapid cargo capture

Mogre

Christensen

Reck-Peterson

et al. 2021

Preprint

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Cellular functions such as autophagy, cell signaling and vesicular trafficking involve the retrograde transport of motor-driven cargo along microtubules. Typically, newly formed cargo engages in slow diffusive movement from its point of origin before attaching to a microtubule. In some cell types, cargo destined for delivery to the perinuclear region relies on capture at dynein-enriched loading zones located near microtubule plus-ends. Such systems include extended cell regions of neurites and fungal hyphae, where the efficiency of the initial diffusive loading process depends on the axial distribution of microtubule plus-ends relative to the initial cargo position. We use analytic mean first passage time calculations and numerical simulations to model diffusive capture processes in tubular cells, exploring how the spatial arrangement of microtubule plus-ends affects the efficiency of retrograde cargo transport. Our model delineates the key features of optimal microtubule arrangements that minimize mean cargo capture times. Namely, we show that configurations with a single long microtubule and broad distribution of additional microtubule plus-ends allow for efficient capture in a variety of different scenarios for retrograde transport. Live-cell imaging of microtubule plus-ends in Aspergillus nidulans hyphae indicates that their distributions exhibit these optimal qualitative features. Our results highlight important coupling effects between microtubule length distribution and retrograde cargo transport, providing guiding principles for the spatial arrangement of microtubules within tubular cell regions.

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“…A hitchhiking cargo, rather than connecting directly to an adaptor-motor complex, instead achieves motility by attaching itself to another motile-competent cargo ( Salogiannis and Reck-Peterson, 2017 ). Hitchhiking represents a mechanism that could be employed to move many cargoes by a small number of motor-bound cargoes in organisms with few genetically encoded motors and cargo adaptors ( Lin et al , 2016 ; Mogre et al , 2020 ).…”

Section: Introductionmentioning

confidence: 99%

PxdA interacts with the DipA phosphatase to regulate peroxisome hitchhiking on early endosomes

Salogiannis

Christensen

Songster

et al. 2021

MBoC

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In canonical microtubule-based transport, adaptor proteins link cargos to dynein and kinesin motors. Recently, an alternative mode of transport known as ‘hitchhiking’ was discovered, where cargos achieve motility by hitching a ride on already-motile cargos, rather than attaching to a motor protein. Hitchhiking has been best-studied in two filamentous fungi, Aspergillus nidulans and Ustilago maydis. In U. maydis, ribonucleoprotein complexes, peroxisomes, lipid droplets, and endoplasmic reticulum hitchhike on early endosomes. In A. nidulans, peroxisomes hitchhike using a putative molecular linker, PxdA, which associates with early endosomes. However, whether other organelles use PxdA to hitchhike on early endosomes is unclear, as are the molecular mechanisms that regulate hitchhiking. Here we find that the proper distribution of lipid droplets, mitochondria and pre-autophagosomes do not require PxdA, suggesting that PxdA is a peroxisome-specific molecular linker. We identify two new pxdA alleles, including a point mutation (R2044P) that disrupts PxdA's ability to associate with early endosomes and reduces peroxisome movement. We also identify a novel regulator of peroxisome hitchhiking, the phosphatase DipA. DipA co-localizes with early endosomes and its early endosome-association relies on PxdA. Together, our data suggest that PxdA and the DipA phosphatase are specific regulators of peroxisome hitchhiking on early endosomes. [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text]

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Hitching a Ride: Mechanics of Transport Initiation through Linker-Mediated Hitchhiking

Cited by 21 publications

References 60 publications

Diffusive search and trajectories on tubular networks: a propagator approach

Diffusive search and trajectories on tubular networks: a propagator approach

Optimizing microtubule arrangements for rapid cargo capture

PxdA interacts with the DipA phosphatase to regulate peroxisome hitchhiking on early endosomes

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