Forces and Disease: Electrostatic force differences caused by mutations in kinesin motor domains can distinguish between disease-causing and non-disease-causing mutations

Lin Li,Zhe Jia,Joshua Alper,Emil Alexov,Subash Godar,Shaolei Teng,Ivan Getov,Yunhui Peng

doi:10.1038/s41598-017-08419-7

Lin Li, Zhe Jia + Show 6 more

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https://doi.org/10.1038/s41598-017-08419-7

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Journal: Scientific Reports	Publication Date: Aug 15, 2017
Citations: 24	License type: open-access

Affiliation: Clemson University, Howard University

Abstract

The ability to predict if a given mutation is disease-causing or not has enormous potential to impact human health. Typically, these predictions are made by assessing the effects of mutation on macromolecular stability and amino acid conservation. Here we report a novel feature: the electrostatic component of the force acting between a kinesin motor domain and tubulin. We demonstrate that changes in the electrostatic component of the binding force are able to discriminate between disease-causing and non-disease-causing mutations found in human kinesin motor domains using the receiver operating characteristic (ROC). Because diseases may originate from multiple effects not related to kinesin-microtubule binding, the prediction rate of 0.843 area under the ROC plot due to the change in magnitude of the electrostatic force alone is remarkable. These results reflect the dependence of kinesin’s function on motility along the microtubule, which suggests a precise balance of microtubule binding forces is required.

Highlights

The ability to predict if genetic mutations cause disease or not has enormous potential to impact human health[1, 2]
We found that the binding funnel is common to kinesins, as shown for kinesin-13 as an example (Fig. 1), and that the electrostatic force guides the kinesin to the binding pocket of the tubulin
We found that the magnitude of the mean electrostatic force, |Favg|, for the 10 wild type kinesins used in this study in the bound state was 1,450 ± 170 pN

Summary

Introduction

The ability to predict if genetic mutations cause disease or not has enormous potential to impact human health[1, 2] Efforts to make these predictions to date have largely been done by assessing the effect of a genetic mutation on the coded protein’s stability and amino acid conservation[3, 4]. The kinesin superfamily of microtubule motor proteins is responsible for a diverse set of cell biological functions including intracellular transport, ciliary assembly, mitosis, meiosis, cytoskeletal morphology, and microtubule dynamics regulation[8, 9]. These functions depend on kinesin’s force generating and motile properties[10, 11]. Electrostatic forces likely underlie the diffusive motility of kinesin-826, 27 and kinesin-1316

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