scholarly journals Diffusion of kinesin motors on cargo can enhance binding and run lengths during intracellular transport

2021 ◽  
pp. mbc.E20-10-0658
Author(s):  
Matthew Bovyn ◽  
Babu Reddy ◽  
Steven Gross ◽  
Jun Allard
Keyword(s):  
Computational Model ◽  
Molecular Motors ◽  
Lipid Droplets ◽  
Intracellular Transport ◽  
Control Point ◽  
Computational Studies ◽  
Organizational Changes ◽  
Surface Mobility ◽  
Viscosity Effects ◽  
Run Lengths

Cellular cargos, including lipid droplets and mitochondria, are transported along microtubules using molecular motors such as kinesins. Many experimental and computational studies focused on cargos with rigidly attached motors, in contrast to many biological cargos that have lipid surfaces that may allow surface mobility of motors. We extend a mechanochemical 3D computational model by adding coupled-viscosity effects to compare different motor arrangements and mobilities. We show that organizational changes can optimize for different objectives: Cargos with clustered motors are transported efficiently, but are slow to bind to microtubules, whereas those with motors dispersed rigidly on their surface bind microtubules quickly, but are transported inefficiently. Finally, cargos with freely-diffusing motors have both fast binding and efficient transport, although less efficient than clustered motors. These results suggest that experimentally observed changes in motor organization may be a control point for transport. [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text]

scholarly journals Diffusion of kinesin motors on cargo can enhance binding and run lengths during intracellular transport

2019 ◽  
Author(s):  
Matthew Bovyn ◽  
Babu Reddy ◽  
Steven Gross ◽  
Jun Allard
Keyword(s):  
Computational Model ◽  
Molecular Motors ◽  
Lipid Droplets ◽  
Intracellular Transport ◽  
Control Point ◽  
Computational Studies ◽  
Organizational Changes ◽  
Surface Mobility ◽  
Viscosity Effects ◽  
Run Lengths

Cellular cargos, including lipid droplets and mitochondria, are transported along microtubules using molecular motors such as kinesins. Many experimental and computational studies of cargos with rigidly attached motors, in contrast to many biological cargos that have lipid surfaces that may allow surface mobility of motors. We extend a mechanochemical 3D computational model by adding coupled-viscosity effects to compare different motor arrangements and mobilities. We show that organizational changes can optimize for different objectives: Cargos with clustered motors are transported efficiently, but are slow to bind to microtubules, whereas those with motors dispersed rigidly on their surface bind microtubules quickly, but are transported inefficiently. Finally, cargos with freely-diffusing motors have both fast binding and efficient transport, although less efficient than clustered motors. These results suggest that experimentally observed changes in motor organization may be a control point for transport.

scholarly journals Peroxisomes, lipid droplets, and endoplasmic reticulum “hitchhike” on motile early endosomes

2015 ◽  
Vol 211 (5) ◽  
pp. 945-954 ◽  
Author(s):  
Sofia C. Guimaraes ◽  
Martin Schuster ◽  
Ewa Bielska ◽  
Gulay Dagdas ◽  
Sreedhar Kilaru ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Molecular Motors ◽  
Lipid Droplets ◽  
Intracellular Transport ◽  
Model System ◽  
Directed Transport ◽  
Intracellular Movement ◽  
Early Endosomes ◽  
Dependent Transport ◽  
First Time

Intracellular transport is mediated by molecular motors that bind cargo to be transported along the cytoskeleton. Here, we report, for the first time, that peroxisomes (POs), lipid droplets (LDs), and the endoplasmic reticulum (ER) rely on early endosomes (EEs) for intracellular movement in a fungal model system. We show that POs undergo kinesin-3– and dynein-dependent transport along microtubules. Surprisingly, kinesin-3 does not colocalize with POs. Instead, the motor moves EEs that drag the POs through the cell. PO motility is abolished when EE motility is blocked in various mutants. Most LD and ER motility also depends on EE motility, whereas mitochondria move independently of EEs. Covisualization studies show that EE-mediated ER motility is not required for PO or LD movement, suggesting that the organelles interact with EEs independently. In the absence of EE motility, POs and LDs cluster at the growing tip, whereas ER is partially retracted to subapical regions. Collectively, our results show that moving EEs interact transiently with other organelles, thereby mediating their directed transport and distribution in the cell.

scholarly journals Interactions of Lipid Droplets with the Intracellular Transport Machinery

2021 ◽  
Vol 22 (5) ◽  
pp. 2776
Author(s):  
Selma Yilmaz Dejgaard ◽  
John F. Presley
Keyword(s):  
Membrane Trafficking ◽  
Lipid Droplets ◽  
Intracellular Transport ◽  
Neutral Lipids ◽  
Small Gtpases ◽  
Lipid Phase ◽  
Intracellular Organelles ◽  
And Function ◽  
Lipid Phase Separation ◽  
Endocytic Pathways

Historically, studies of intracellular membrane trafficking have focused on the secretory and endocytic pathways and their major organelles. However, these pathways are also directly implicated in the biogenesis and function of other important intracellular organelles, the best studied of which are peroxisomes and lipid droplets. There is a large recent body of work on these organelles, which have resulted in the introduction of new paradigms regarding the roles of membrane trafficking organelles. In this review, we discuss the roles of membrane trafficking in the life cycle of lipid droplets. This includes the complementary roles of lipid phase separation and proteins in the biogenesis of lipid droplets from endoplasmic reticulum (ER) membranes, and the attachment of mature lipid droplets to membranes by lipidic bridges and by more conventional protein tethers. We also discuss the catabolism of neutral lipids, which in part results from the interaction of lipid droplets with cytosolic molecules, but with important roles for both macroautophagy and microautophagy. Finally, we address their eventual demise, which involves interactions with the autophagocytotic machinery. We pay particular attention to the roles of small GTPases, particularly Rab18, in these processes.

ATGL-mediated triglyceride turnover and the regulation of mitochondrial capacity in skeletal muscle

2015 ◽  
Vol 308 (11) ◽  
pp. E960-E970 ◽  
Author(s):  
Ruth C. R. Meex ◽  
Andrew J. Hoy ◽  
Rachael M. Mason ◽  
Sheree D. Martin ◽  
Sean L. McGee ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Lipid Droplets ◽  
Target Genes ◽  
Control Point ◽  
Hormone Sensitive Lipase ◽  
Acid Oxidation ◽  
Minor Importance ◽  
Transcriptional Responses ◽  
Mitochondrial Capacity

Emerging evidence indicates that skeletal muscle lipid droplets are an important control point for intracellular lipid homeostasis and that regulating fatty acid fluxes from lipid droplets might influence mitochondrial capacity. We used pharmacological blockers of the major triglyceride lipases, adipose triglyceride lipase (ATGL) and hormone-sensitive lipase, to show that a large proportion of the fatty acids that are transported into myotubes are trafficked through the intramyocellular triglyceride pool. We next tested whether increasing lipolysis from intramyocellular lipid droplets could activate transcriptional responses to enhance mitochondrial and fatty acid oxidative capacity. ATGL was overexpressed by adenoviral and adenoassociated viral infection in C2C12 myotubes and the tibialis anterior muscle of C57Bl/6 mice, respectively. ATGL overexpression in C2C12 myotubes increased lipolysis, which was associated with increased peroxisome proliferator-activated receptor (PPAR)-∂ activity, transcriptional upregulation of some PPAR∂ target genes, and enhanced mitochondrial capacity. The transcriptional responses were specific to ATGL actions and not a generalized increase in fatty acid flux in the myotubes. Marked ATGL overexpression (20-fold) induced modest molecular changes in the skeletal muscle of mice, but these effects were not sufficient to alter fatty acid oxidation. Together, these data demonstrate the importance of lipid droplets for myocellular fatty acid trafficking and the capacity to modulate mitochondrial capacity by enhancing lipid droplet lipolysis in vitro; however, this adaptive program is of minor importance when superimposing the normal metabolic stresses encountered in free-moving animals.

scholarly journals Bacterial Microtubules Exhibit Polarized Growth, Mixed-Polarity Bundling, and Destabilization by GTP Hydrolysis

2017 ◽  
Author(s):  
César Díaz-Celis ◽  
Viviana I. Risca ◽  
Felipe Hurtado ◽  
Jessica K. Polka ◽  
Scott D. Hansen ◽  
...  
Keyword(s):  
Molecular Motors ◽  
Intracellular Transport ◽  
Complex Dynamics ◽  
Critical Concentration ◽  
Polarized Growth ◽  
Gtp Hydrolysis ◽  
Filament Dynamics ◽  
Mixed Polarity ◽  
Self Association

AbstractBacteria of the genusProsthecobacterexpress homologs of eukaryotic α-and β-tubulin, called BtubA and BtubB, that have been observed to assemble into bacterial microtubules (bMTs). ThebtubABgenes likely entered theProsthecobacterlineage via horizontal gene transfer and may derive from an early ancestor of the modern eukaryotic microtubule (MT). Previous biochemical studies revealed that BtubA/B polymerization is GTP-dependent and reversible and that BtubA/B folding does not require chaperones. To better understand bMT behavior and gain insight into the evolution of microtubule dynamics, we characterizedin vitrobMT assembly using a combination of polymerization kinetics assays, and microscopy. Like eukaryotic microtubules, bMTs exhibit polarized growth with different assembly rates at each end. GTP hydrolysis stimulated by bMT polymerization drives a stochastic mechanism of bMT disassembly that occurs via polymer breakage. We also observed treadmilling (continuous addition and loss of subunits at opposite ends) of bMT fragments. Unlike MTs, polymerization of bMTs requires KCl, which reduces the critical concentration for BtubA/B assembly and induces bMTs to form stable mixed-orientation bundles in the absence of any additional bMT-binding proteins. Our results suggest that at potassium concentrations resembling that inside the cytoplasm ofProsthecobacter, bMT stabilization through self-association may be a default behavior. The complex dynamics we observe in both stabilized and unstabilized bMTs may reflect common properties of an ancestral eukaryotic tubulin polymer.ImportanceMicrotubules are polymers within all eukaryotic cells that perform critical functions: they segregate chromosomes in cell division, organize intracellular transport by serving as tracks for molecular motors, and support the flagella that allow sperm to swim. These functions rely on microtubules remarkable range of tunable dynamic behaviors. Recently discovered bacterial microtubules composed of an evolutionarily related protein are evolved from a missing link in microtubule evolution, the ancestral eukaryotic tubulin polymer. Using microscopy and biochemical approaches to characterize bacterial microtubules, we observed that they exhibit complex and structurally polarized dynamic behavior like eukaryotic microtubules, but differ in how they self-associate into bundles and become destabilized. Our results demonstrate the diversity of mechanisms that microtubule-like filaments employ to promote filament dynamics and monomer turnover.

scholarly journals Peroxisomes move by hitchhiking on early endosomes using the novel linker protein PxdA

2015 ◽  
Author(s):  
John Salogiannis ◽  
Martin J. Egan ◽  
Samara L. Reck-Peterson
Keyword(s):  
Molecular Motors ◽  
Intracellular Transport ◽  
Coiled Coil ◽  
Leading Edge ◽  
Time Lapse ◽  
Early Endosome ◽  
Organelle Transport ◽  
The Novel ◽  
Coiled Coil Region ◽  
Early Endosomes

Eukaryotic cells use microtubule-based intracellular transport for the delivery of many subcellular cargos, including organelles. The canonical view of organelle transport is that organelles directly recruit molecular motors via cargo-specific adaptors. In contrast to this view, we show here that peroxisomes move by hitchhiking on early endosomes, an organelle that directly recruits the transport machinery. Using the filamentous fungus Aspergillus nidulans we find that hitchhiking is mediated by a novel endosome-associated linker protein, PxdA. PxdA is required for normal distribution and long-range movement of peroxisomes, but not early endosomes or nuclei. Using simultaneous time-lapse imaging we find that early endosome-associated PxdA localizes to the leading edge of moving peroxisomes. We identify a coiled-coil region within PxdA that is necessary and sufficient for early endosome localization and peroxisome distribution and motility. These results present a new mechanism of microtubule-based organelle transport where peroxisomes hitchhike on early endosomes and identify PxdA as the novel linker protein required for this coupling.

Computational analysis of hereditary spastic paraplegia mutations in the kinesin motor domains of KIF1A and KIF5A

2020 ◽  
Vol 19 (06) ◽  
pp. 2041003
Author(s):  
Vidhyanand Mahase ◽  
Adebiyi Sobitan ◽  
Christina Johnson ◽  
Farion Cooper ◽  
Yixin Xie ◽  
...  
Keyword(s):  
Free Energy ◽  
Protein Stability ◽  
Molecular Motors ◽  
Intracellular Transport ◽  
Computational Analysis ◽  
Binding Free Energy ◽  
Membrane Vesicles ◽  
Energy Calculation ◽  
Missense Mutations ◽  
Kinesin Motor

Hereditary spastic paraplegias (HSPs) are a genetically heterogeneous collection of neurodegenerative disorders categorized by progressive lower-limb spasticity and frailty. The complex HSP forms are characterized by various neurological features including progressive spastic weakness, urinary sphincter dysfunction, extra pyramidal signs and intellectual disability (ID). The kinesin superfamily proteins (KIFs) are microtubule-dependent molecular motors involved in intracellular transport. Kinesins directionally transport membrane vesicles, protein complexes, and mRNAs along neurites, thus playing important roles in neuronal development and function. Recent genetic studies have identified kinesin mutations in patients with HSPs. In this study, we used the computational approaches to investigate the 40 missense mutations associated with HSP and ID in KIF1A and KIF5A. We performed homology modeling to construct the structures of kinesin–microtubule binding domain and kinesin–tubulin complex. We applied structure-based energy calculation methods to determine the effects of missense mutations on protein stability and protein–protein interaction. The results revealed that the most of disease-causing mutations could change the folding free energy of kinesin motor domain and the binding free energy of kinesin–tubulin complex. We found that E253K associated with ID in KIF1A decrease the protein stability of kinesin motor domains. We showed that the HSP mutations located in kinesin–tubulin complex interface, such as K253N and R280C in KIF5A, can destabilize the kinesin–tubulin complex. The computational analysis provides useful information for understanding the roles of kinesin mutations in the development of ID and HSPs.

Application of Quasi-Steady-State Methods to Nonlinear Models of Intracellular Transport by Molecular Motors

2017 ◽  
Vol 79 (9) ◽  
pp. 1923-1978 ◽  
Author(s):  
Cole Zmurchok ◽  
Tim Small ◽  
Michael J. Ward ◽  
Leah Edelstein-Keshet
Keyword(s):  
Steady State ◽  
Molecular Motors ◽  
Intracellular Transport ◽  
Nonlinear Models ◽  
Quasi Steady State

scholarly journals Run length distribution of dimerized kinesin-3 molecular motors: comparison with dimeric kinesin-1

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Si-Kao Guo ◽  
Xiao-Xuan Shi ◽  
Peng-Ye Wang ◽  
Ping Xie
Keyword(s):  
Molecular Motors ◽  
Average Run Length ◽  
Length Distribution ◽  
Dissociation Rate ◽  
Run Length ◽  
Proposed Model ◽  
Run Length Distribution ◽  
Run Lengths ◽  
Kinesin Superfamily ◽  
Single Exponential

AbstractKinesin-3 and kinesin-1 molecular motors are two families of the kinesin superfamily. It has been experimentally revealed that in monomeric state kinesin-3 is inactive in motility and cargo-mediated dimerization results in superprocessive motion, with an average run length being more than 10-fold longer than that of kinesin-1. In contrast to kinesin-1 showing normally single-exponential distribution of run lengths, dimerized kinesin-3 shows puzzlingly Gaussian distribution of run lengths. Here, based on our proposed model, we studied computationally the dynamics of kinesin-3 and compared with that of kinesin-1, explaining quantitatively the available experimental data and revealing the origin of superprocessivity and Gaussian run length distribution of kinesin-3. Moreover, predicted results are provided on ATP-concentration dependence of run length distribution and force dependence of mean run length and dissociation rate of kinesin-3.

scholarly journals Dynamic Force Adaptation of Lipid Droplets during Intracellular Transport in Cos1 Cells

2013 ◽  
Vol 104 (2) ◽  
pp. 475a
Author(s):  
Babu Reddy Janakaloti Narayanareddy ◽  
Preetha Anand ◽  
Steven P. Gross
Keyword(s):  
Lipid Droplets ◽  
Intracellular Transport ◽  
Dynamic Force
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