Next Article in Journal
Long Chain Fatty Acid Acylated Derivatives of Quercetin-3-O-Glucoside as Antioxidants to Prevent Lipid Oxidation
Next Article in Special Issue
Amino Acid Distribution Rules Predict Protein Fold: Protein Grammar for Beta-Strand Sandwich-Like Structures
Previous Article in Journal
Nuclear Transport of Yeast Proteasomes
Previous Article in Special Issue
Local Order in the Unfolded State: Conformational Biases and Nearest Neighbor Interactions
Article Menu

Export Article

Open AccessArticle
Biomolecules 2014, 4(4), 956-979; doi:10.3390/biom4040956

Probing the Kinetic Stabilities of Friedreich’s Ataxia Clinical Variants Using a Solid Phase GroEL Chaperonin Capture Platform

1
Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Av. da República, EAN, Oeiras 2784-505, Portugal
2
Department of Biochemistry and Molecular Biology, Hemenway Life Sciences Innovation Center (HLSIC), University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA
These authors contributed equally to this work.
Current address: Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 East California Blvd., Pasadena, CA 91125, USA
§
Current address: Department of Chemical and Biomolecular Engineering, University of Delaware, Newark, DE 19716, USA
*
Authors to whom correspondence should be addressed.
Received: 5 February 2014 / Revised: 29 August 2014 / Accepted: 19 September 2014 / Published: 20 October 2014
(This article belongs to the Special Issue Protein Folding and Misfolding)
View Full-Text   |   Download PDF [67855 KB, uploaded 20 October 2014]   |  

Abstract

Numerous human diseases are caused by protein folding defects where the protein may become more susceptible to degradation or aggregation. Aberrant protein folding can affect the kinetic stability of the proteins even if these proteins appear to be soluble in vivo. Experimental discrimination between functional properly folded and misfolded nonfunctional conformers is not always straightforward at near physiological conditions. The differences in the kinetic behavior of two initially folded frataxin clinical variants were examined using a high affinity chaperonin kinetic trap approach at 25 °C. The kinetically stable wild type frataxin (FXN) shows no visible partitioning onto the chaperonin. In contrast, the clinical variants FXN-p.Asp122Tyr and FXN-p.Ile154Phe kinetically populate partial folded forms that tightly bind the GroEL chaperonin platform. The initially soluble FXN-p.Ile154Phe variant partitions onto GroEL more rapidly and is more kinetically liable. These differences in kinetic stability were confirmed using differential scanning fluorimetry. The kinetic and aggregation stability differences of these variants may lead to the distinct functional impairments described in Friedreich’s ataxia, the neurodegenerative disease associated to frataxin functional deficiency. This chaperonin platform approach may be useful for identifying small molecule stabilizers since stabilizing ligands to frataxin variants should lead to a concomitant decrease in chaperonin binding. View Full-Text
Keywords: clinical mutants; missense mutants; frataxin; Friedreich’s ataxia; protein folding; chaperonin; osmolytes; protein stability; protein misfolding and misfolding diseases clinical mutants; missense mutants; frataxin; Friedreich’s ataxia; protein folding; chaperonin; osmolytes; protein stability; protein misfolding and misfolding diseases
Figures

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

Supplementary material

Scifeed alert for new publications

Never miss any articles matching your research from any publisher
  • Get alerts for new papers matching your research
  • Find out the new papers from selected authors
  • Updated daily for 49'000+ journals and 6000+ publishers
  • Define your Scifeed now

SciFeed Share & Cite This Article

MDPI and ACS Style

Correia, A.R.; Naik, S.; Fisher, M.T.; Gomes, C.M. Probing the Kinetic Stabilities of Friedreich’s Ataxia Clinical Variants Using a Solid Phase GroEL Chaperonin Capture Platform. Biomolecules 2014, 4, 956-979.

Show more citation formats Show less citations formats

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]
Biomolecules EISSN 2218-273X Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top