Interrogating Emergent Transport Properties for Molecular Motor Ensembles: A Semi-analytical Approach

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.

Engineering Heterodimeric Kinesins through Genetic Incorporation of Noncanonical Amino Acids

“…Nevertheless, one can easily adapt our method to engineer novel heterodimers to gain new insights into the motility mechanisms and functions of different kinesins. For example, a kinesin heterodimer with two nonidentical neck linkers that differ in length and/or amino acid composition would be an extremely useful reagent for dissecting the mechanical role of the neck linker, and crippled kinesin heterodimers can be used to further understand how kinesins coordinate in multimotor ensembles to achieve optimal efficiency. − Due to the advantages of a heterolinker of tunable composition and length, which is reactive toward two different ncAA-containing proteins, this method should allow exploration of a variety of engineered heteroprotein complexes.…”

Stiffness of Cargo–Motor Linkage Tunes Myosin VI Motility and Response to Load

“…Cytoskeletal motors link to their cellular cargoes through diverse mechanisms ranging from adaptor protein intermediates to lipid molecules that directly bind the motor. , The diversity in cargo–motor attachments translates into distinct linkage stiffness regimes in cellular membrane traffic. Both experimental − and theoretical studies − have shown that linkage stiffness alters motile properties, such as the velocity and run length of cytoskeletal motors. However, the mechanistic basis of these changes, in terms of stepping behavior and force generation, is not well understood and is the focus of this study.…”

Coherent light scattering from cellular dynamics in living tissues

“…For instance, molecular motors can participate in cancer processes, such as a possible connection between KIF11 and prostate cancer [50], and between KIF11 and Taxol resistance [51]. Molecular motors also can participate in neurogenerative disease, such as a functional interaction between kinesin-I and amyloid precursor protein in Alzheimer's disease [52], in phosphorylation in Huntington's disease [53], and in axonal transport in Alzheimer's disease [54,55]. Metabolism is central to all cellular processes, and modifications in motors can affect dynamin and glucose uptake [56] and mitochondrial fusion and fission [57].…”