Interrogating Emergent Transport Properties for Molecular Motor Ensembles: A Semi-analytical Approach.
Intracellular transport is an essential function in eucaryotic cells, facilitated by motor proteins-proteins converting chemical energy into kinetic energy. It is understood that motor proteins work in teams enabling unidirectional and bidirectional transport of intracellular cargo over long distances. Disruptions of the underlying transport mechanisms, often caused by mutations that alter single motor characteristics, are known to cause neurodegenerative diseases. For example, phosphorylation of kinesin motor domain at the serine residue is implicated in Huntington's disease, with a recent study of phosphorylated and phosphomimetic serine residues indicating lowered single motor stalling forces. In this article we report the effects of mutations of this nature on transport properties of cargo carried by multiple wild-type and mutant motors. Results indicate that mutants with altered stall forces might determine the average velocity and run-length even when they are outnumbered by wild type motors in the ensemble. It is shown that mutants gain a competitive advantage and lead to an increase in the expected run-length when the load on the cargo is in the vicinity of the mutant's stalling force or a multiple of its stalling force. A separate contribution of this article is the development of a semi-analytic method to analyze transport of cargo by multiple motors of multiple types. The technique determines transition rates between various relative configurations of motors carrying the cargo using the transition rates between various absolute configurations. This enables a computation of biologically relevant quantities like average velocity and run-length without resorting to Monte Carlo simulations. It can also be used to introduce alterations of various single motor parameters to model a mutation and to deduce effects of such alterations on the transport of a common cargo by multiple motors. Our method is easily implementable and we provide a software package for general use.
Department of Electrical Engineering, University of Minnesota Twin Cities, Minneapolis, Minnesota, United States of America.
Shreyas
http://orcid.org/0000-0001-9265-1617
S
Bhaban
Department of Electrical Engineering and Computer Science, University of Tennessee Knoxville, Knoxville, Tennessee, United States of America.
Donatello
D
Materassi
Department of Genetics, Cell Biology, and Development, University of Minnesota Twin Cities, Minneapolis, Minnesota, United States of America.
Mingang
M
Li
Department of Genetics, Cell Biology, and Development, University of Minnesota Twin Cities, Minneapolis, Minnesota, United States of America.
Thomas
T
Hays
Department of Electrical Engineering, University of Minnesota Twin Cities, Minneapolis, Minnesota, United States of America.
Murti
M
Salapaka
D001665:Binding Sites; D001693:Biological Transport, Active / Q000502:physiology; D003198:Computer Simulation; D004735:Energy Transfer / Q000502:physiology; D008870:Microtubules / Q000737:chemistry* / Q000502:physiology*; D008954:Models, Biological; D008956:Models, Chemical; D015233:Models, Statistical; D020409:Molecular Motor Proteins / Q000737:chemistry* / Q000502:physiology*; D009038:Motion; D011485:Protein Binding
D020409:Molecular Motor Proteins