Abstract
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.
Highlights
Motor proteins- kinesin, dynein and myosins- are nanoscale machines that are the main effectors of intracellular transport
In our analysis we considered cargoes transported by the following motor ensembles: cargo with two wild-type (WW) motors, one wild-type and one mutant (WM) motors, two mutant (MM) motors, three wild-type (WWW) motors, two wild-type and one mutant (WWM) motors, one wild-type and two mutant (WMM)motors, and three mutant (MMM) motors
The analysis indicates that when the cargo has two wild type motors attached (WW case), the probability that both motors remain attached to the microtubule peaks when load force is close to 12pN
Summary
Motor proteins- kinesin, dynein and myosins- are nanoscale machines that are the main effectors of intracellular transport. They play a critical role in the growth and sustenance of healthy cells by enabling a transport of intracellular cargo over networks of microtubules [1]. The mechano-chemical behavior of a single motor moving along the microtubule substrate to transport a cargo is relatively well understood [4]. In [22], Gross and coworkers employed Monte-Carlo simulation studies built on a model of a single kinesin in to explore how multiple identical kinesin motors might interact to transport a cargo against a hindering load force. At decreased levels of ATP concentration, the velocities of cargoes transported by single and two motor proteins decreases
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