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

TL;DR

This paper investigates how single motor mutations affect the collective transport properties of motor protein ensembles, revealing that mutants with altered stall forces can dominate cargo transport even when outnumbered.

Contribution

It introduces a semi-analytic method to analyze multi-motor cargo transport, allowing precise computation of velocity and run-length, and models mutation effects on transport dynamics.

Findings

Mutants with altered stall forces influence ensemble velocity and run-length.

Mutants gain advantage and increase run-length near their stalling force.

Developed a software package for the semi-analytic transport analysis.

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.