Biology subjects

McKinley, S. A.

Publications and source records attributed to McKinley, S. A..

3 recordsLinked to original sources

bioRxiv2024

DNA tensiometer reveals catch-bond detachment kinetics of kinesin-1, -2 and -3

Bidirectional cargo transport by kinesin and dynein is essential for cell viability, and defects are linked to neurodegenerative disease. Computational models predict that load-dependent motor detachment strongly determines the outcome of kinesin-dynein tug-of-war, with kinesin-3 and kinesin-2 more load-sensitive than kinesin-1. Yet reconstituted assays show that all three kinesin families compete similarly well against dynein. Previous work demonstrated that vertical forces from optical trapping assays can enhance kinesin-1 dissociation, suggesting that motor behavior may depend strongly on cargo geometry. To measure kinesin detachment and reattachment kinetics under forces applied parallel to the microtubule, we developed a DNA-based tensiometer using an entropic DNA spring linking motors to microtubules. For kinesin-1, -2, and -3, dissociation rates at stall were slower than during unloaded motion, and reattachment kinetics were consistent with a weakly bound slip state preceding detachment. Kinesin-3 behavior further suggested that long KIF1A run lengths arise from multiple short runs connected by diffusive episodes. Stochastic simulations reproduced the measured load-dependent kinetics and enabled direct comparison of transition rates among kinesin families. These results provide insight into how kinesin-1, -2 and -3 transport cargo in complex cellular geometries and compete against dynein during bidirectional transport. Impact StatementAll three kinesin transport families exhibit unexpectedly slow dissociation under load, explaining robust competition with dynein during bidirectional cargo transport.

biophysics↗

bioRxiv2018

Antibody-mediated immobilization of virions in mucus

Antibodies have been shown to hinder the movement of Herpes Simplex Virus (HSV) virions in cervicovaginal mucus (CVM), as well as other viruses in other mucus secretions. However, it has not been possible to directly observe the mechanisms underlying this phenomenon, so the nature of virion-antibody-mucin interactions remain poorly understood. In this work, we analyzed thousands of virion traces from single particle tracking experiments to explicate how antibodies must cooperate to immobilize virions for relatively long time periods. First, using a clustering analysis, we observed a clear separation between two classes of virion behavior: Freely Diffusing and Immobilized. While the proportion of Freely Diffusing virions decreased with antibody concentration, the magnitude of their diffusivity did not, implying an all-or-nothing dichotomy in the pathwise effect of the antibodies. Proceeding under the assumption that all binding events are reversible, we used a novel switch-point detection method to conclude that there are very few, if any, state-switches on the experimental time scale of twenty seconds. To understand this slow state-switching, we analyzed a recently proposed continuous-time Markov chain model for binding kinetics and virion movement. Model analysis implied that virion immobilization requires cooperation by multiple antibodies that are simultaneously bound to the virion and mucin matrix, and that there is an entanglement phenomenon that accelerates antibody-mucin binding when a virion is immobilized. In addition to developing a widely-applicable framework for analyzing multi-state particle behavior, this work substantially enhances our mechanistic understanding of how antibodies can reinforce a mucus barrier against passive invasive species.

immunology↗

bioRxiv2016

Resource-Driven Encounters and the Induction of Disease Among Consumers

Submitted Manuscript 2016. Territorial animals share a variety of common resources, which can be a major driver of conspecific encounter rates. We examine how changes in resource availability influence the rate of encounters among individuals in a consumer population by implementing a spatially explicit model for resource visitation behavior by consumers. Using data from 2009 and 2010 in Etosha National Park, we verify our model's prediction that there is a saturation effect in the expected number of jackals that visit a given carcass site as carcasses become abundant. However, this does not directly imply that the overall resource-driven encounter rate among jackals decreases. This is because the increase in available carcasses is accompanied by an increase in the number of jackals that detect and potentially visit carcasses. Using simulations and mathematical analysis of our consumer-resource interaction model, we characterize key features of the relationship between resource-driven encounter rate and model parameters. These results are used to investigate a standing hypothesis that the outbreak of a fatal disease among zebras can potentially lead to an outbreak of an entirely different disease in the jackal population, a process we refer to as indirect induction of disease.

ecology↗