title: The lower limits for protein stability and foldability in primary hyperoxaluria type I.
abstract: Mutational effects on protein stability and foldability are important to understand conformational diseases and protein evolution. In this work, we perform a comprehensive investigation on the energetic basis underlying mutational effects on the stability of human alanine:glyoxylate aminotransferase (AGT). We study twenty two variants whose kinetic stabilities span over eleven orders of magnitude and are classified into two groups: i) ten naturally-occurring variants, including the most common mutations causing primary hyperoxaluria type I (PH1); and ii) twelve consensus variants obtained by sequence-alignment statistics. We show that AGT dimer stability determines denaturation rates, and mutations modulate stability by changes in the effective thermodynamic stability, the aggregation propensity of partially/globally unfolded states and subtle energetic changes in the rate-limiting denaturation step. In combination with our previous expression analyses in eukaryotic cells, we propose the existence of two lower limits for AGT stability, one linked to optimal folding efficiency (close to the major allele stability) and the other setting a minimal efficiency compatible with glyoxylate detoxification in vivo (close to the minor allele stability). These lower limits could explain the high prevalence of misfolding as a disease mechanism in PH1 and support the use of pharmacological ligands aimed to increase AGT stability as therapies for this disease.
authors.affiliation: Departamento de Química-Física, Facultad de Ciencias, Universidad de Granada, E-18071 Granada, Spain.
authors.forename: Noel
authors.initials: N
authors.lastname: Mesa-Torres
authors.affiliation: Hospital Universitario de Canarias, Universidad La Laguna, Centre for Biomedical Research on Rare Diseases (CIBERER), Tenerife E-38320, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Salido
authors.affiliation: Departamento de Química-Física, Facultad de Ciencias, Universidad de Granada, E-18071 Granada, Spain. Electronic address: angelpey@ugr.es.
authors.forename: Angel L
authors.initials: AL
authors.lastname: Pey
keywords: Differential scanning calorimetry; Misfolding disease; Molecular chaperone; Protein denaturation energetics; Protein foldability; Protein kinetic stability