Equilibrium thermodynamic analysis of amyotrophic lateral sclerosis-associated mutant Apo Cu,Zn superoxide dismutases
Equilibrium thermodynamic analysis of amyotrophic lateral sclerosis-associated mutant Apo Cu,Zn superoxide dismutases
Engineering Village 2
? 2006 Elsevier Inc
Accession number: 06259946950
Title: Equilibrium thermodynamic analysis of amyotrophic lateral sclerosis-associated mutant Apo Cu,Zn superoxide dismutases
Authors: Vassall, Kenrick A.; Stathopulos, Peter B.; Rumfeldt, Jessica A. O.; Lepock, James R.; Meiering, Elizabeth M.
Author affiliation: Guelph-Waterloo Centre for Graduate Work in Chemistry and Biochemistry, Department of Chemistry and Biology, University of Waterloo, Waterloo, Ont. N2L 3G1, Canada
Serial title: Biochemistry
Abbreviated serial title: Biochemistry
Volume: v 45
Issue: n 23
Issue date: Jun 13 2006
Publication year: 2006
Pages: p 7366-7379
Language: English
ISSN: 0006-2960
CODEN: BICHAW
Document type: Journal article (JA)
Publisher: American Chemical Society, Columbus, OH 43210-3337, United States
Abstract: The folding and thermodynamic properties of metal free (apo) superoxide dismutases (SODs) are systematically analyzed using equilibrium guanidinium chloride (GdmCl) curves and differential scanning calorimetry (DSC). Chemically and structurally diverse amyotrophic lateral sclerosis (ALS)-associated mutations (G85R, G93R, E100G, I113T) are introduced into a pseudo-wild-type background that has no free cysteines, resulting in highly reversible unfolding. Analysis of the protein concentration dependence of GdmCl curves reveals formation of a monomer intermediate in equilibrium with native dimer and unfolded monomer. Global fitting of the data enables quantitative measurement of free energy changes for both dimer dissociation and monomer intermediate stability. All the mutations decrease protein stability, mainly by destabilizing the monomer intermediate, but also by tending to weaken dimerization, even for mutations far from the dimer interface. Thus, the effects of mutations seem to propagate through the apo protein, and result in increased population of both intermediate and unfolded monomers. This may underlie increased formation of toxic aggregates by mutants in ALS. Analysis of DSC data for apo SODs is consistent with stability measurements from GdmC1 curves and provides further evidence for increased aggregation by mutant proteins through increased ratios of van't Hoff to calorimetric enthalpies of unfolding. ? 2006 American Chemical Society.
Number of references: 67
Ei main heading: Mutagenesis
Ei controlled terms: Thermodynamic properties - Copper - Zinc - Differential scanning calorimetry - Monomers - Free energy - Biochemistry - Dimerization - Proteins - Enthalpy
Uncontrolled terms: Amyotrophic lateral sclerosis - Global fitting - Calorimetric enthalpies - Superoxide dismutases (SOD)
Ei classification codes: 461.8.1 Genetic Engineering - 641.1 Thermodynamics - 544.1 Copper - 546.3 Zinc & Alloys - 944.6 Temperature Measurements - 804 Chemical Products Generally - 801.2 Biochemistry - 815.2 Polymerization - 804.1 Organic Compounds
Treatment: Literature review (LIT); Experimental (EXP)
DOI: 10.1021/bi0600953
Database: Compendex
Compilation and indexing terms, ? 2006 Elsevier Inc. All rights reserved
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