Bulletin of the American Physical Society
APS March Meeting 2018
Volume 63, Number 1
Monday–Friday, March 5–9, 2018; Los Angeles, California
Session E51: Physics of Intracellular TransportFocus
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Sponsoring Units: DBIO DFD Chair: Jing Xu, Univ of California - Merced Room: LACC 511C |
Tuesday, March 6, 2018 8:00AM - 8:36AM |
E51.00001: Dynamics of the intraflagellar transport machinery at the ciliary tip Invited Speaker: Ahmet Yildiz Cilia (and flagella) are hair-like organelles that extend from the plasma membrane of nearly all mammalian cells for sensory and motile functions. The assembly and maintenance of all cilia require intraflagellar transport (IFT) of its building blocks from the cell body to its tip. These cargoes bind to IFT complexes that are organized into larger IFT trains as they enter the cilium, transported to ciliary tip along axonemal microtubules by the kinesin-II motor. Once the trains reach the tip, they are reorganized and transported back to the ciliary base by dynein-1b. Due to the traffic jam of multiple trains at the ciliary tip, how IFT trains are remodeled in these turnaround zones cannot be determined by conventional imaging. Using Photogate imaging, we visualized the full range of movement of single IFT trains and motors in Chlamydomonas flagella. This revealed that at the tip of the flagellum, IFT trains split apart and mix with each other to assemble into new trains, which move back to the base. Kinesin-II carries dynein to the tip as inactive cargo, detaches from IFT trains at the tip and diffuses in the flagellum. As the flagellum grows longer, diffusion delays return of kinesin-II to the basal body, depleting kinesin-II available for transport of new material to the tip. Our results suggest that dissociation of kinesin-II from IFT trains serves as a negative feedback mechanism that facilitates flagellar length control in Chlamydomonas. |
Tuesday, March 6, 2018 8:36AM - 8:48AM |
E51.00002: Motors and Forces from a Theoretical Perspective Florian Berger, Lu Rao, Arne Gennerich, Abdullah Chaudhary, Adam Hendricks, A.J. Hudspeth Forces influence molecular motors on different length scales. At the level of a single motor head, force controls the binding affinity of the associated microfilament or microtubule, an effect that is important for the coordination of conformational changes and enzymatic reactions. On a larger scale, at which motor molecules cooperate either to transport cargos or to generate tension, forces between the motors contribute to the dynamics of such ensembles.We use stochastic descriptions based on finite Markov chains to study motor molecules on these different scales. For single dynein heads we deduce the force-dependent strength of microtubule binding from distributions of unbinding forces measured in optical traps. On the scale of intracellular transport, we extend a stochastic tug-of-war description to explain the bidirectional motility of phagosomes driven by kinesin-1, kinesin-2, and dynein. To understand how forces and nucleotide concentrations regulate the elasticity of a small ensemble of myosin Ic molecules, we introduce a thermodynamically consistent chemomechanical cycle of myosin Ic and integrate it into an ensemble description. |
Tuesday, March 6, 2018 8:48AM - 9:00AM |
E51.00003: Brownian Dynamics Simulation Reveals How Properties of the Cargo and its Environment Can Influence Multiple Motor Transport Matthew Bovyn, Steven Gross, Jun Allard Active transport of subcellular cargos along microtubules is essential for organization and function of eukaryotic cells. While we understand much about how single motors are able to generate force to accomplish this transport, it is still unclear how these motors work in the small groups often present on cellular cargos. Furthermore, little is understood about how properties of the cargo itself and properties of its environment can influence how cargos are transported. To investigate how these properties may influence transport in the cell, we developed a 3D Brownian dynamics simulator of cargo transport which includes cargo shape and motor location on the cargo. The end goal of the simulator is to study cargo dynamics in complex microtubule networks, including at microtubule intersections, and to decipher the effects of cargo composition, including surface-fluid properties of vesicular cargos and lipid droplets, which have previously been challenging to simulate. Simulations reveal that changes in cargo or environment properties can drive cargos toward distinct transport outcomes, opening the way for environment-based cargo sorting and, ultimately, navigation and cell-scale spatial organization. |
Tuesday, March 6, 2018 9:00AM - 9:12AM |
E51.00004: A Fluid Membrane Enhances The Velocity of Cargo Transport by Small Teams of Kinesin-1 Qiaochu Li, Kuo-fu Tseng, stephen King, Weihong Qiu, Jing Xu Kinesin-1 is a major molecular motor driving the fundamental process of transport in live cells. While the single-molecule functions of kinesin are well characterized, the physiologically relevant transport of membranous cargos by small teams of kinesins remains poorly understood. A key experimental challenge remains in the quantitative control of the number of motors driving transport. Here we utilized “motile fraction” to overcome this challenge, and experimentally accessed transport by a single kinesin through the physiologically relevant transport by a small team of kinesins. We used a fluid lipid bilayer to model the cellular membrane in vitro, and employed optical trapping to quantify transport of membrane-enclosed cargos versus traditional membrane-free cargos under otherwise identical conditions. We found that coupling motors via a fluid membrane significantly enhances the velocity of cargo transport by small teams of kinesins; this velocity enhancement arises from altered interactions between kinesins. Our study demonstrates that membrane-based coupling between motors is a key determinant of kinesin-based transport. Enhanced velocity may be critical for the timely delivery of cargos in live cells. |
Tuesday, March 6, 2018 9:12AM - 9:24AM |
E51.00005: Analytical Aspects of Molecular Motor Ensemble Dynamics Shreyas Bhaban, Saurav Talukdar, James Melbourne, Murti Salapaka The functioning and survival of eukaryotic cells is critically dependent on intracellular transport, a process mainly enabled by molecular motors. The transport is often facilitated by teams of multiple motors, possibly of the same or different kind. Understanding how various motors in a team interact to carry cargoes against varying load forces can shed light on underlying mechanisms of intracellular transport. Numerous theoretical studies have resorted to monte-carlo or semi-analytical based models to draw insightful inferences. We utilize semi-analytic methods and Markov models for the analysis, by investigating the relative arrangements of the motors ferrying common cargo. Our study suggests that the motor-cargo assembly is a robust system, with motors adopting unique steady state relative configurations. The configurations are affected by numerous external factors, including load forces on the cargo. Under low loads, motors do not conform to any particular arrangements, but tend to cluster together under increasing loads. Under high loads, similar to sudden obstacles, motors favor configurations that aid immediate cargo translocation once the load has subsided. We present extensive mathematical proofs for a general case of any (finite) number of motors carrying the cargo. |
Tuesday, March 6, 2018 9:24AM - 10:00AM |
E51.00006: Design principles for intracellular road networks Invited Speaker: Ajay Gopinathan Intracellular transport of vesicles and organelles is typically carried out by a combination of diffusion and active, motor-driven transport along networks of actin and microtubule cytoskeletal filaments. Perturbations to transport can significantly impact cellular viability and can result in disease at the organismal scale. While much work in the past has focused on how motor properties affect transport, there has been growing interest in how the architecture and properties of the cytoskeletal network influence transport. Network features, characterized by the density, lengths, locations, orientations, and connectivity of filaments, as well as defects and blockades along them likely influences intracellular transport in much the same way that road connectivity and conditions are critical determinants of vehicular traffic. In this talk, I shall focus on some recent work that highlights the importance of these features. At the level of a single filament, I shall discuss how defects and obstacles along the filament can manifest themselves in anomalous transport properties. At the network scale, I will argue that that the actual architecture of the network is critical. I will discuss how, for example, particular filament arrangements can result in “traps” near the nucleus that result in highly variable transport times, while other architectures result in rapid directed transport. In all cases, I shall highlight some potential strategies that cells can exploit to promote efficient and robust transport. |
Tuesday, March 6, 2018 10:00AM - 10:12AM |
E51.00007: Effect of confinement and cargo mechanical properties on motor-driven cargo transport Kevin Ching, Supravat Dey, Moumita Das Intracellular transport of cargo by molecular motors is essential for cells to function properly. Cargoes, such as vesicles and organelles, are transported by molecular motors to their correct locations via a combination of active motion on microtubule filaments and passive Brownian motion. During this process, the motor-cargo complex has to navigate the crowded and confining environment of the surrounding biopolymer networks. Additionally, cargos are rarely carried by a single motor and motor-motor interactions may occur during collective transport of cargos. However, most existing models of cargo transport have focused on the dilute limit of a single or a few motors transporting cargo along a single immobilized microtubule. Here we mathematically model cargo transport on a microtubule within a confining filament network using numerical simulations and analytical calculations. We study average displacements, mean squared displacements, and average velocities for different cases, such as single/multiple motor(s) transporting cargo, different cargo sizes, and different confinement widths. Our results may help to elucidate the impact of the cytoskeletal network and cargo mechanical properties on intracellular cargo transport. |
Tuesday, March 6, 2018 10:12AM - 10:24AM |
E51.00008: Multi-modal stochastic transport in tubular cells Saurabh Mogre, Elena Koslover Eukaryotic cells utilize a variety of mechanisms to transport particles of different sizes throughout the cytoplasm. Commonly employed transport modes include diffusion driven by stochastic fluctuations in the medium, processive motor-driven transport along cytoskeletal tracks, and advection in a flowing cytoplasmic fluid. We use analytical theory and simulations to explore the efficiency and relative contributions of these different modes of transport. Focusing on tubular geometries such as those found in fungal hyphae and neuronal axons, we highlight the potential importance of hydrodynamic entrainment in the cytoplasm as well as the interplay between diffusive and processive motion in efficiently dispersing and delivering organelles within the cell. We quantify the consequences of tethering to microtubule tracks, deriving a simple expression for the parameter regime where tethering can aid or hinder overall transport efficiency. For the example system of peroxisome transport in hyphae, we show that both passive diffusion and directed "hitch-hiking" runs contribute substantially to the organelles' ability to efficiently find intracellular targets, while tethering aids in the initial establishment of a uniform organelle distribution. |
Tuesday, March 6, 2018 10:24AM - 10:36AM |
E51.00009: The effect of system dimensionality on the motility of burnt-bridges ratchets Chapin Korosec, Martin Zuckermann, Nancy Forde The burnt-bridges ratchet (BBR) mechanism is a model for biased molecular motion whereby a random walker destroys substrate sites as it moves, thereby inhibiting backwards stepping. Nature has been shown to employ the BBR mechanism in a variety of processes, most notably the segregation of low-copy-number plasmids and the degradation of human collagen by matrix metalloproteinases. In this talk I will present the results of kinetic Monte Carlo simulations that predict the ensemble-average dynamics of polyvalent BBRs. One anticipates that, as the track dimensionality increases, there is increased opportunity to switch directions thereby diminishing ballistic-like behaviour. However, we find that a strictly one-dimensional track is not required to enforce ballistic motion; there exists a tolerance window in track dimensionality that allows for ballistic-like behaviour that is a function of the length and number of catalytic legs. We also find that fixing the leg length and increasing the number of legs results in earlier detachment, but higher directionality. Our results offer insights to design principles for polyvalent BBRs implemented in the lab, where experimentalists seek to engineer artificial systems that exploit reactivity with the track to achieve directed transport. |
Tuesday, March 6, 2018 10:36AM - 10:48AM |
E51.00010: Selective-plane illumination microscopy to characterize diffusion of DNA in cytoskeletal networks Devynn Wulstein, Kathryn Regan, Shea Ricketts, Rae Anderson, Ryan McGorty How polymers such as DNA move through crowded cytoskeletal environments has yet to be fully understood. New techniques to quantitatively characterize how the dynamics may differ from simple diffusion and to link those anomalous dynamics of DNA to properties of the crowding cytoskeletal network are required. Here we demonstrate a technique that measures the ensemble and single molecule dynamics over a large range of time and length scales. We use selective-plane illumination microscopy (SPIM) to observe the dynamics of fluorescently labeled DNA molecules in varying networks of actin and microtubules. Due to the Gaussian nature of the excitation light-sheet, we use single molecule tracking in the region with high optical sectioning and capture ensemble dynamics in the regions with low optical sectioning. We use differential dynamic microscopy (DDM) to analyze ensemble dynamics. Using SPIM and DDM, we efficiently obtain single-molecule and ensemble dynamics from the same time-series of images. Additionally, we can image and measure the dynamics of the three-dimensional network. Our use of single-molecule tracking and DDM on the same image acquired with SPIM could be extended to characterizing in vivo dynamics or other complex fluids with non-ergodic behavior. |
Tuesday, March 6, 2018 10:48AM - 11:00AM |
E51.00011: Doppler Spectroscopy of Intracellular Dynamics Inside Intact 3D Tissue David Nolte, Zhe Li, Honggu Choi, John Turek Intracellular dynamics are dominated by active transport driven by energetic processes far from equilibrium. Cytoskeletal restructuring, membrane motions and molecular motors use GTP and ATP to drive directed transport that is quasi-one-dimensional and produces lifetime-broadened Doppler light scattering. A new functional imaging approach called biodynamic imaging (BDI) uses low-coherence 3D digital holography to capture dynamic speckle fluctuations caused by the multiple interferences among Doppler frequencies. The omega-tau product provides a natural dividing line between Doppler and diffusive regimes, with a broad cross-over range into which many tissue-based light scattering processes fall. This talk describes the biophysical origins of fluctuation spectra from intracellular transport. Biodynamic imaging, based on changes in intracellular dynamics caused by applied therapeutics or changing environments, is expanding into multiple applications, including the selection of chemotherapy for personalized cancer care, screening of potential new therapeutics, and the selection of embryos for artificial reproductive technology. See https://works.bepress.com/ddnolte/. |
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