Cholesterol in the cargo membrane amplifies tau inhibition of kinesin-1-based transport.

Intracellular cargos are often membrane-enclosed and transported by microtubule-based motors in the presence of microtubule-associated proteins (MAPs). Whereas increasing evidence reveals how MAPs impact the interactions between motors and microtubules, critical questions remain about the impact of the cargo membrane on transport. Here we combined in vitro optical trapping with theoretical approaches to determine the effect of a lipid cargo membrane on kinesin-based transport in the presence of MAP tau. Our results demonstrate that attaching kinesin to a fluid lipid membrane reduces the inhibitory effect of tau on kinesin. Moreover, adding cholesterol, which reduces kinesin diffusion in the cargo membrane, amplifies the inhibitory effect of tau on kinesin binding in a dosage-dependent manner. We propose that reduction of kinesin diffusion in the cargo membrane underlies the effect of cholesterol on kinesin binding in the presence of tau, and we provide a simple model for this proposed mechanism. Our study establishes a direct link between cargo membrane cholesterol and MAP-based regulation of kinesin-1. The cholesterol effects uncovered here may more broadly extend to other lipid alterations that impact motor diffusion in the cargo membrane, including those associated with aging and neurological diseases.

Evolution of evolvability in rapidly adapting populations.

Mutations can alter the short-term fitness of an organism, as well as the rates and benefits of future mutations. While numerous examples of these evolvability modifiers have been observed in rapidly adapting microbial populations, existing theory struggles to predict when they will be favoured by natural selection. Here we develop a mathematical framework for predicting the fates of genetic variants that modify the rates and benefits of future mutations in linked genomic regions. We derive analytical expressions showing how the fixation probabilities of these variants depend on the size of the population and the diversity of competing mutations. We find that competition between linked mutations can dramatically enhance selection for modifiers that increase the benefits of future mutations, even when they impose a strong direct cost on fitness. However, we also find that modest direct benefits can be sufficient to drive evolutionary dead ends to fixation. Our results suggest that subtle differences in evolvability could play an important role in shaping the long-term success of genetic variants in rapidly evolving microbial populations.