期刊
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
卷 1832, 期 12, 页码 2277-2288出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbadis.2013.09.002
关键词
Primary Hyperoxaluria; Alanine:glyoxylate aminotransferase; Pyridoxal phosphate; Hereditary metabolic disease; Protein aggregation; Protein misfolding
资金
- Telethon Foundation [GPP10092]
- Hyperoxaluria and Oxalosis Foundation
- Elena Polishchuk and Simona Iacobacci (TIGEM, Naples)
- Telethon Electron Microscopy Core Facility (IBP, CNR, Naples) (Telethon) [GTF08001]
Primary Hyperoxaluria Type I (PHI) is a severe rare disorder of metabolism due to inherited mutations on liver peroxisomal alanine:glyoxylate aminotransferase (AGT), a pyridoxal 5'-phosphate (PLP)-dependent enzyme whose deficiency causes the deposition of calcium oxalate crystals in the kidneys and urinary tract. PHI is an,extremely heterogeneous disease and there are more than 150 disease-causing mutations currently known, most of which are missense mutations. Moreover, the molecular mechanisms by which missense mutations lead to AGT deficiency span from structural, functional to subcellular localization defects. Gly161 is a highly conserved residue whose mutation to Arg, Cys or Ser is associated with PHI. Here we investigated the molecular bases of the AGT deficit caused by Gly161 mutations with expression studies in a mammalian cellular system paired with biochemical analyses on the purified recombinant proteins. Our results show that the mutations of Gly161 (i) strongly reduce the expression levels and the intracellular half-life of AGT, and (ii) make the protein in the apo-form prone to an electrostatically-driven aggregation in the cell cytosol. The coenzyme PLP, by shifting the equilibrium from the apo- to the holo-form, is able to reduce the aggregation propensity of the variants, thus partly decreasing the effect of the mutations. Altogether, these results shed light on the mechanistic details underlying the pathogenicity of Gly161 variants, thus expanding our knowledge of the enzymatic phenotypes leading to AGT deficiency. (C) 2013 Elsevier B.V. All rights reserved.
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