Insights into the pathogenesis of primary hyperoxaluria type I from the structural dynamics of alanine:glyoxylate aminotransferase variants.

Autor: Vankova P; Institute of Biotechnology - BioCeV, Academy of Sciences of the Czech Republic, Vestec, Czech Republic., Pacheco-Garcia JL; Departamento de Química Física, Universidad de Granada, Spain., Loginov DS; Institute of Microbiology - BioCeV, Academy of Sciences of the Czech Republic, Vestec, Czech Republic., Gómez-Mulas A; Departamento de Química Física, Universidad de Granada, Spain., Kádek A; Institute of Microbiology - BioCeV, Academy of Sciences of the Czech Republic, Vestec, Czech Republic., Martín-Garcia JM; Department of Crystallography & Structural Biology, Institute of Physical Chemistry Blas Cabrera, Spanish National Research Council (CSIC), Madrid, Spain., Salido E; Center for Rare Diseases (CIBERER), Hospital Universitario de Canarias, Universidad de la Laguna, Tenerife, Spain., Man P; Institute of Microbiology - BioCeV, Academy of Sciences of the Czech Republic, Vestec, Czech Republic., Pey AL; Departamento de Química Física, Unidad de Excelencia en Química Aplicada a Biomedicina y Medioambiente e Instituto de Biotecnología, Universidad de Granada, Spain.
Jazyk: angličtina
Zdroj: FEBS letters [FEBS Lett] 2024 Feb; Vol. 598 (4), pp. 485-499. Date of Electronic Publication: 2024 Jan 19.
DOI: 10.1002/1873-3468.14800
Abstrakt: Primary hyperoxaluria type I (PH1) is caused by deficient alanine:glyoxylate aminotransferase (AGT) activity. PH1-causing mutations in AGT lead to protein mistargeting and aggregation. Here, we use hydrogen-deuterium exchange (HDX) to characterize the wild-type (WT), the LM (a polymorphism frequent in PH1 patients) and the LM G170R (the most common mutation in PH1) variants of AGT. We provide the first experimental analysis of AGT structural dynamics, showing that stability is heterogeneous in the native state and providing a blueprint for frustrated regions with potentially functional relevance. The LM and LM G170R variants only show local destabilization. Enzymatic transamination of the pyridoxal 5-phosphate cofactor bound to AGT hardly affects stability. Our study, thus, supports that AGT misfolding is not caused by dramatic effects on structural dynamics.
(© 2024 Federation of European Biochemical Societies.)
Databáze: MEDLINE
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