Modeling the Bidirectional Transport of Intracellular Cargos by Oppositely-directed Motor Proteins

Open Access
Author:
Mentley, Brandon Scott
Area of Honors:
Bioengineering
Degree:
Bachelor of Science
Document Type:
Thesis
Thesis Supervisors:
  • William O Hancock, Thesis Supervisor
  • William O Hancock, Honors Advisor
  • John Fricks, Faculty Reader
Keywords:
  • kinesin
  • dynein
  • motor protein
  • bidirectional transport
  • matlab
  • simulation
Abstract:
Transport of intracellular cargos is achieved through the combined efforts of kinesin and dynein motor proteins. This transport is characterized by periods of processive movement, as well as frequent pauses and switches in direction. Currently, the interactions between kinesins and dyneins bound to the same cargo are described as a direct mechanical competition between the two motor protein superfamilies. However, this “tug-of-war model” fails to explain experimental observations that show that inhibiting either kinesin or dynein results in reduced motility for both motor species. Three additional models have been proposed in an attempt to overcome the shortcomings of the tug-of-war model. The “microtubule tethering model” proposes a diffusive state in which motors are loosely associated with the microtubule, thus anchoring the cargo while providing minimal resistance to stepping by oppositely-directed motors. The “mechanical activation model” states that motor proteins tend to remain in an inhibited state unless a hindering force, such as the force exerted by an oppositely-directed motor, is applied. Lastly, the “steric disinhibition model” states that motor proteins tend to remain in an autoinhibited state unless they are bound at some site by oppositely-directed motors or regulatory proteins. This goal of this project was to produce computational simulations of the competing models describing bidirectional transport by kinesin and dynein. Analysis of these simulations has already revealed that the mechanical activation model displays a number of characteristics seen in experimental data, including pauses and, most importantly, the paradox of codependence, which is the phenomenon that inhibition of one motor species results in reduced motility in both directions. In the future, the simulations will be used to determine the direction of experiments that will hopefully validate one of the proposed models and lead to a greater understanding of bidirectional transport.