Emergent Transport Properties of Molecular Motor Ensemble Affected by Single Motor Mutations

📝 Abstract

Intracellular transport is an essential function in eucaryotic cells, facilitated by motor proteins - proteins converting chemical energy into kinetic energy. It is known 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 expected run-length when 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 exact computation of average velocity and run-length. 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.

💡 Analysis

Intracellular transport is an essential function in eucaryotic cells, facilitated by motor proteins - proteins converting chemical energy into kinetic energy. It is known 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 expected run-length when 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 exact computation of average velocity and run-length. 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.

📄 Content

Emergent Transport Properties of Molecular Motor Ensemble Affected by Single Motor Mutations Shreyas Bhaban∗1, Donatello Materassi2, Mingang Li3, Thomas Hays3, and Murti Salapaka1 1Department of Electrical Engineering, University of Minnesota-Twin Cities, Minneapolis MN 55455, USA 2Department of Electrical Engineering and Computer Science,University of Tennessee-Knoxville, Knoxville, TN 37996, USA 2Department of Genetics, Cell Biology, and Development,University of Minnesota-Twin Cities, Minneapolis MN 55455, USA Abstract Intracellular transport is an essential function in eucaryotic cells, facilitated by motor proteins - pro- teins 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 mo- tor 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 an exact computation of biologically relevant quantities like average velocity and run-length. 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. ∗bhaba001@umn.edu 1 Introduction 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 en- abling a transport of intracellular cargo over networks of microtubules [1]. Disruption of the functions performed by these molecular motors is linked to neurodegenerative diseases such as Huntington’s, Parkinson’s and Alzheimer’s Disease [2, 3], muscular disorders such as heart disease, uterine com- plications and high blood pressure. The mechano-chemical behavior of a single motor moving along the microtubule substrate to transport a cargo is relatively well understood [4]. However in vivo it is known that multiple motors work in teams to transport a common cargo [5]; how multiple motor- proteins coordinate to transport a common cargo is not well understood [5, 6, 7]. Many studies employ a probabilistic description of the behavior of a single motor protein to construct models that describe how multiple motors transport a common cargo [5, 8, 9, 10]. In [11], 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. Their work indicates, counter intuitively, the existence of a form of strain-gating, where the motors of an ensemble share loads unequally enabling cargo transport over longer distances. Xu and coworkers examined the effects of ATP concentration on the transport of cargo carried by single and two motors in [12]. At decreased levels of ATP concentration, the velocities of cargoes transported by single and two motor proteins decreases. Coincidentally at decreased ATP concentration there was an an appreciable increase in the run-length of cargoes transported by two motors, while no such effect was seen in the case of transport by one motor. The authors proposed that the increased run-length observed in the presence of two motors results from the lowered dissociation of each motor from the microtubule at decreased ATP concentrations and the increased probability that the cargo stayed bound to the microtubule. Studies such as [10, 13] using probabilistic models of single motors have also predicted in that an ensemble of kinesin motors is a robust system and the robustness increases under high loads [14]. The study of cargo transport by a heterogeneous ensemble of

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