Title
Potential complementation effects of two disease-associated mutations in tetrameric glutaryl-CoA dehydrogenase is due to inter subunit stability-activity counterbalance
Author
Joana V. Ribeiro, Tânia G. Lucas, Peter Bross, Cláudio M. Gomes, Bárbara J. Henriques
Year
2019
Journal
Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics
Abstract
Glutaric Aciduria Type I (GA-I), is an autosomal recessive neurometabolic disease caused by mutations in the GCDH gene that encodes for glutaryl-CoA dehydrogenase (GCDH), a flavoprotein involved in the metabolism of tryptophan, lysine and hydroxylysine. Although over 200 disease mutations have been reported a clear correlation between genotype and phenotype has been difficult to establish. To contribute to a better molecular understanding of GA-I we undertook a detailed molecular study on two GCDH disease-related variants, GCDH-p.Arg227Pro and GCDH-p.Val400Met. Heterozygous patients harbouring these two mutations have increased residual enzymatic activity in relation to homozygous patients with only one of the mutations, suggesting a complementation effect between the two.
Instrument
J-1500, FP-8200
Keywords
Circular dichroism, Secondary structure, Fluorescence, Protein structure, Thermal stability, Protein folding, Ligand binding, Protein stability, Kinetics, Biochemistry