Multimotor Transport in a System of Active and Inactive Kinesin-1 Motors

Abstract

Long-range directional transport in cells is facilitated by microtubule-based motor proteins. One example is transport in a nerve cell, where small groups of motor proteins, such as kinesins and cytoplasmic dynein, work together to ensure the supply and clearance of cellular material along the axon. Defects in axonal transport have been linked to Alzheimer's and other neurodegenerative diseases. However, it is not known in detail how multimotor-based cargo transport is impaired if a fraction of the motors are defective. To mimic impaired multimotor transport in vitro, we performed gliding motility assays with varying fractions of active kinesin-1 motors and inactive kinesin-1 motor mutants. We found that impaired transport manifests in multiple motility regimes: 1), a fast-motility regime characterized by gliding at velocities close to the single-molecule velocity of the active motors; 2), a slow-motility regime characterized by gliding at close-to zero velocity or full stopping; and 3), a regime in which fast and slow motilities coexist. Notably, the transition from the fast to the slow regime occurred sharply at a threshold fraction of active motors. Based on single-motor parameters, we developed a stochastic model and a mean-field theoretical description that explain our experimental findings. Our results demonstrate that impaired multimotor transport mostly occurs in an either/or fashion: depending on the ratio of active to inactive motors, transport is either performed at close to full speed or is out of action.

Neurofilaments and Neurofilament Proteins in Health and Disease

“…However, an alternative view coming from computational modeling by Mitchell and Lee suggests that a single motor can carry an NF and that no cooperativity is required to produce the slow-transport velocity profile (Mitchell and Lee 2009). In contrast, cooperativity is required to produce the experimental velocity profiles for fast transport (Mitchell and Lee 2009), consistent with evidence that the average velocity of gliding MTs can transition from slow to fast, depending on the number of active motors engaged (Scharrel et al 2014), and that larger organelle cargoes require multiple motors for fast transport (Kural et al 2005). The enrichment of kinesin in fast axonal transport is consistent with the computational modeling of Mitchell and Lee (Elluru et al 1995).…”

Kinesin-1 Motors Can Circumvent Permanent Roadblocks by Side-Shifting to Neighboring Protofilaments

“…This renders their interaction with motors more intricate as they may also get removed or pushed aside by the motors. Our studies performed with static, permanent roadblocks may thus not be universally applicable to all obstacles, however, will bear relevance for some of them among which are inactive motors (31).…”

Collective dynamics of processive cytoskeletal motors

“…48,49,71–73 This problem is important for understanding mechanisms of heterozygous genetic disorders where mixtures of mutated and wild type motor proteins function together. 4,74 It may also be relevant for cancer treatments that target motor proteins, that likely produce mixed populations of inhibited and uninhibited motors.…”