Please use this identifier to cite or link to this item: http://repositorio.unicamp.br/jspui/handle/REPOSIP/339695
Type: Artigo
Title: Mechanistic insights revealed by a UBE2A mutation linked to intellectual disability
Author: de Oliveira, Juliana Ferreira
Vital do Prado, Paula Favoretti
da Costa, Silvia Souza
Sforca, Mauricio Luis
Canateli, Camila
Ranzani, Americo Tavares
Maschietto, Mariana
Lopes de Oliveira, Paulo Sergio
Otto, Paulo A.
Klevit, Rachel E.
Victorino Krepischi, Ana Cristina
Rosenberg, Carla
Franchini, Kleber Gomes
Abstract: Ubiquitin-conjugating enzymes (E2) enable protein ubiquitination by conjugating ubiquitin to their catalytic cysteine for subsequent transfer to a target lysine side chain. Deprotonation of the incoming lysine enables its nucleophilicity, but determinants of lysine activation remain poorly understood. We report a novel pathogenic mutation in the E2 UBE2A, identified in two brothers with mild intellectual disability. The pathogenic Q93E mutation yields UBE2A with impaired aminolysis activity but no loss of the ability to be conjugated with ubiquitin. Importantly, the low intrinsic reactivity of UBE2A Q93E was not overcome by a cognate ubiquitin E3 ligase, RAD18, with the UBE2A target PCNA. However, UBE2A Q93E was reactive at high pH or with a lowpK a amine as the nucleophile, thus providing the first evidence of reversion of a defective UBE2A mutation. We propose that Q93E substitution perturbs the UBE2A catalytic microenvironment essential for lysine deprotonation during ubiquitin transfer, thus generating an enzyme that is disabled but not dead
Subject: Deficiencia intelectual
Ubiquitina
Rights: Fechado
Identifier DOI: 10.1038/s41589-018-0177-2
Address: https://www.nature.com/articles/s41589-018-0177-2
Date Issue: 2019
Appears in Collections:FCM - Artigos e Outros Documentos

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