Publications

Authors:

Oppici, Elisa; Roncador, Alessandro; Montioli, Riccardo; Bianconi, Silvia; Cellini, Barbara

Title:

Gly161 mutations associated with Primary Hyperoxaluria Type I induce the cytosolic aggregation and the intracellular degradation of the apo-form of alanine:glyoxylate aminotransferase

Year:

2013

Type of item:

Articolo in Rivista

Tipologia ANVUR:

Articolo su rivista

Language:

Inglese

Format:

A Stampa

Referee:

Sì

Name of journal:

BBA

ISSN of journal:

0925-4439

N° Volume:

1832

Number or Folder:

12

Page numbers:

2277-2288

Keyword:

PRIMARY HYPEROXALURIA; alanine:glyoxylate aminotransferase; protein aggregation; pathogenic variants

Short description of contents:

Primary Hyperoxaluria Type I (PH1) 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. PH1 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 PH1. 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.

Product ID:

78014

Handle IRIS:

11562/622968

Deposited On:

October 22, 2013

Last Modified:

November 15, 2022

Bibliographic citation:

Oppici, Elisa; Roncador, Alessandro; Montioli, Riccardo; Bianconi, Silvia; Cellini, Barbara, Gly161 mutations associated with Primary Hyperoxaluria Type I induce the cytosolic aggregation and the intracellular degradation of the apo-form of alanine:glyoxylate aminotransferase «BBA» , vol. 1832 , n. 12 , 2013 , pp. 2277-2288

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