Cooperative responses of multiple kinesins to variable and constant loads.
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ABSTRACT:
SUBMITTER: Jamison DK
PROVIDER: S-EPMC3270990 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Kinesins are nano-sized biological motors which walk by repeating a mechanochemical cycle. A single kinesin molecule is able to transport its cargo about 1 μm in the absence of external loads. However, kinesins perform much longer range transport in cells by working collectively. This long range of transport by a team of kinesins is surprising because the motion of the cargo in cells can be hindered by other particles. To reveal how the kinesins are able to accomplish their tasks of transport in harsh intracellular circumstances, stochastic studies on the kinesin motion are performed by considering the binding and unbinding of kinesins to microtubules and their dependence on the force acting on kinesin molecules. The unbinding probabilities corresponding to each mechanochemical state of kinesin are modeled. The statistical characterization of the instants and locations of binding are captured by computing the probability of unbound kinesin being at given locations. It is predicted that a group of kinesins has a more efficient transport than a single kinesin from the perspective of velocity and run length. Particularly, when large loads are applied, the leading kinesin remains bound to the microtubule for long time which increases the chances of the other kinesins to bind to the microtubule. To predict effects of this behavior of the leading kinesin under large loads on the collective transport, the motion of the cargo is studied when the cargo confronts obstacles. The result suggests that the behavior of kinesins under large loads prevents the early termination of the transport which can be caused by the interference with the static or moving obstacles.
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Project description:We develop a stochastic model for variable-length stepping of kinesins engineered with extended neck linkers. This requires that we consider the separation in microtubule binding sites between the heads of the motor at the beginning of a step. We show that this separation is stationary and can be included in the calculation of standard experimental quantities. We also develop a corresponding matrix computational framework for conducting computer experiments. Our matrix approach is more efficient computationally than large-scale Monte Carlo simulation. This efficiency greatly eases sensitivity analysis, an important feature when there is considerable uncertainty in the physical parameters of the system. We demonstrate the application and effectiveness of our approach by showing that the worm-like chain model for the neck linker can explain recently published experimental data. While we have focused on a particular scenario for kinesins, these methods could also be applied to myosin and other processive motors.
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Project description:How cargoes move within a crowded cell-over long distances and at speeds nearly the same as when moving on unimpeded pathway-has long been mysterious. Through an in vitro force-gliding assay, which involves measuring nanometer displacement and piconewtons of force, we show that multiple mammalian kinesin-1 (from 2 to 8) communicate in a team by inducing tension (up to 4 pN) on the cargo. Kinesins adopt two distinct states, with one-third slowing down the microtubule and two-thirds speeding it up. Resisting kinesins tend to come off more rapidly than, and speed up when pulled by driving kinesins, implying an asymmetric tug-of-war. Furthermore, kinesins dynamically interact to overcome roadblocks, occasionally combining their forces. Consequently, multiple kinesins acting as a team may play a significant role in facilitating smooth cargo motion in a dense environment. This is one of few cases in which single molecule behavior can be connected to ensemble behavior of multiple motors.
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Project description:Quantitative MS assays for Igs are compared with existing clinical methods in samples from patients with plasma cell dyscrasias, for example, multiple myeloma (MM).Using LC-MS/MS data, Ig constant region peptides, and transitions were selected for LC-MRM MS. Quantitative assays were used to assess Igs in serum from 83 patients. RNA sequencing and peptide-based LC-MRM are used to define peptides for quantification of the disease-specific Ig.LC-MRM assays quantify serum levels of Igs and their isoforms (IgG1-4, IgA1-2, IgM, IgD, and IgE, as well as kappa (?) and lambda (?) light chains). LC-MRM quantification has been applied to single samples from a patient cohort and a longitudinal study of an IgE patient undergoing treatment, to enable comparison with existing clinical methods. Proof-of-concept data for defining and monitoring variable region peptides are provided using the H929 MM cell line and two MM patients.LC-MRM assays targeting constant region peptides determine the type and isoform of the involved Ig and quantify its expression; the LC-MRM approach has improved sensitivity compared with the current clinical method, but slightly higher inter-assay variability. Detection of variable region peptides is a promising way to improve Ig quantification, which could produce a dramatic increase in sensitivity over existing methods, and could further complement current clinical techniques.
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Project description:Introduction: Variable power output (VP) is one of the main characteristics of a road cycling mass-start. Tolerating VP during outdoor road cycling highly influences performance. There is a lack of continuous and comprehensive measurements during this power condition. Accordingly, the aim of the present study was to investigate physiological response to VP vs. constant power output (CP) as well as the perceived exertion of these two power conditions, and to investigate if variations in power output which span above lactate threshold (LT), differ from variations below LT. Methods: 15 elite competitive cyclists completed three test days, including 1 day of baseline testing and 2 days of main testing, consisting of four bouts of 28 min at two different intensities, "low" at 70% of LT and "high" at 95% of LT, with VP and CP. VP was performed with a 15% fluctuation of the average power output every second minute. Maximal oxygen uptake (VO2), respiratory exchange ratio (RER), heart rate (HR), blood lactate (LA), rating of perceived exertion (RPE), cadence (RPM) and power output (W) were measured. Results: At both low and high intensity, the VP condition induced a significantly higher VO2, HR and LA than the CP condition. Whole-bout RPE was similar between power conditions at high intensity. Additionally, at the high intensity, cycling with VP led to a greater increase in LA and lesser increase in RPE compared to cycling with CP. Discussion: The results of this study show that, despite considerable differences in the demand during the VP and CP bouts, there are minor differences in the perceptual and physiological response directly following these two power conditions in a cohort of elite competitive cyclists. A practical implication of these findings is that training with VP seems to be a viable alternative to training with CP, at least at high intensity.
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Project description:The adaptive humoral immune response is responsible for the generation of antimicrobial proteins known as immunoglobulin molecules or antibodies. Immunoglobulins provide a defense system against pathogenic microbes and toxins by targeting them for removal and/or destruction. Historically, antibodies have been thought to be composed of distinct structural domains known as the variable and constant regions that are responsible for antigen binding and mediating effector functions such as opsonization and complement activation, respectively. These domains were thought to be structurally and functionally independent. Recent work has revealed however, that in some families of antibodies, the two regions can influence each other. We will discuss the body of work that led to these observations, as well as the mechanisms that have been proposed to explain how these two different antibody regions may interact in the function of antigen binding.
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Project description:Motor proteins are active enzymatic molecules that support important cellular processes by transforming chemical energy into mechanical work. Although the structures and chemomechanical cycles of motor proteins have been extensively investigated, the sensitivity of a motor's velocity in response to a force is not well-understood. For kinesin, velocity is weakly influenced by a small to midrange external force (weak susceptibility) but is steeply reduced by a large force. Here, we utilize a structure-based molecular dynamic simulation to study the molecular origin of the weak susceptibility for a single kinesin. We show that the key step in controlling the velocity of a single kinesin under an external force is the ATP release from the microtubule-bound head. Only under large loading forces can the motor head release ATP at a fast rate, which significantly reduces the velocity of kinesin. It underpins the weak susceptibility that the velocity will not change at small to midrange forces. The molecular origin of this velocity reduction is that the neck linker of a kinesin only detaches from the motor head when pulled by a large force. This prompts the ATP binding site to adopt an open state, favoring ATP release and reducing the velocity. Furthermore, we show that two load-bearing kinesins are incapable of equally sharing the load unless they are very close to each other. As a consequence of the weak susceptibility, the trailing kinesin faces the challenge of catching up to the leading one, which accounts for experimentally observed weak cooperativity of kinesins motors.
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Project description:BackgroundModules of interacting components arranged in specific network topologies have evolved to perform a diverse array of cellular functions. For a network with a constant topological structure, its function within a cell may still be tuned by changing the number of instances of a particular component (e.g., gene copy number) or by modulating the intrinsic biochemical properties of a component (e.g., binding strength or catalytic efficiency). How such perturbations affect cellular response dynamics remains poorly understood. Here, we explored these effects in a common decision-making motif, cross-antagonism with autoregulation, by synthetically constructing this network in yeast.ResultsWe employed the engineering design strategy of reuse to build this topology with a single protein building block, TetR, creating necessary components through TetR mutations and fusion partners. We then studied the impact of several topology-preserving perturbations - strength of cross-antagonism, number of operator sites in a promoter, and gene dosage - on decision-making behavior. We found that reducing TetR repression strength, which hinders cross-antagonism, resulted in a loss of mutually exclusive cell responses. Unexpectedly, increasing the number of operator sites also impeded decision-making exclusivity, which may be a consequence of the averaging effect that arises when multiple transcriptional activators and repressors are accommodated at a given locus. Stochastic simulations of this topology revealed that, even for networks with high TetR repression strength and a low number of operator sites, increasing gene dosage can reduce exclusivity in response dynamics. We further demonstrated this result experimentally by quantifying gene copy numbers in selected yeast clones with differing phenotypic responses.ConclusionsOur study illustrates how parameters that do not change the topological structure of a decision-making network can nonetheless exert significant influence on its response dynamics. These findings should further inform the study of native motifs, including the effects of topology-preserving mutations, and the robust engineering of synthetic networks.
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