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.
Recommended Citation
Jennings, S.; Chenevert, M.; Liu, L.; Mottamal, M..; Wojcik, E. J.; and Huckaba, Thomas M., "Characterization of Kinesin Switch I Mutations that Cause Hereditary Spastic Paraplegia" (2017). Faculty and Staff Publications. 155.
https://digitalcommons.xula.edu/fac_pub/155
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.