Title

Characterization of Kinesin Switch I Mutations that Cause Hereditary Spastic Paraplegia

Funding Source

National Institutes of Health, National Center on Minority Health and Health Disparities, National Institute of General Medical Sciences

Grant Number

2G12MD007595-06, 5UL1GM118967,R01GM066328,P20GM103424

Department

Department of Biology

Document Type

Article

Publication Date

7-2017

Abstract

Kif5A is a neuronally-enriched isoform of the Kinesin-1 family of cellular transport motors. 23 separate mutations in the motor domain of Kif5A have been identified in patients with the complicated form of hereditary spastic paraplegia (HSP). We performed in vitro assays on dimeric recombinant Kif5A with HSP-causing mutations in the Switch I domain, which participates in the coordination and hydrolysis of ATP by kinesin. We observed a variety of significantly reduced catalytic and mechanical activities as a result of each mutation, with the shared phenotype from each that motility was significantly reduced. Substitution of Mn2+ for Mg2+ in our reaction buffers provides a dose-dependent rescue in both the catalytic and ensemble mechanical properties of the S203C mutant. This work provides mechanistic insight into the cause of HSP in patients with these mutations and points to future experiments to further dissect the root cause of this disease.

Comments

DOI: 10.1371/journal.pone.0180353

PubMed ID: 28678816

Funding text

This work was supported by the Louisiana Cancer Research Consortium and the NIH-RCMI grant 2G12MD007595-06 from the National Institutes on Minority Health and Health Disparities to TMH, an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health grant P20GM103424 to TMH, a National Institute of General Medical Sciences of the National Institutes of Health grant 5UL1GM118967 to TMH, and a National Institute of General Medical Sciences of the National Institutes of Health grant R01GM066328 to EJW. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors would like to thank Sunyoung Kim and her laboratory members for guidance and feedback on this project.

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