Mechanistic insights revealed by a UBE2A mutation linked to intellectual disability

Author(s):Show less -

de Oliveira, Juliana Ferreira ^[1] ; Vital do Prado, Paula Favoretti ^[1] ; da Costa, Silvia Souza ^[2] ; Sforca, Mauricio Luis ^[1] ; Canateli, Camila ^[1] ; Ranzani, Americo Tavares ^[1] ; Maschietto, Mariana ^[1] ; Lopes de Oliveira, Paulo Sergio ^[1] ; Otto, Paulo A. ^[2] ; Klevit, Rachel E. ^[3] ; Victorino Krepischi, Ana Cristina ^[2] ; Rosenberg, Carla ^[2] ; Franchini, Kleber Gomes ^{[4, 1]}

Affiliation

^[1] Ctr Res Energy & Mat, Brazilian Biosci Natl Lab, Campinas, SP - Brazil

^[2] Univ Sao Paulo, Inst Biosci, Dept Genet & Evolutionary Biol, Sao Paulo - Brazil

^[3] Univ Washington, Dept Biochem, Seattle, WA 98195 - USA

^[4] Univ Estadual Campinas, Sch Med, Dept Internal Med, Campinas, SP - Brazil

• Document type: Journal article
• Source: Nature Chemical Biology; v. 15, n. 1, p. 62+, JAN 2019.
• Web of Science Citations: 2

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. (AU)

• FAPESP's process: 13/08028-1 - CEGH-CEL - Human Genome and Stem Cell Research Center
• Grantee: Mayana Zatz
• Support type: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 15/06281-7 - Characterization of the epigenetic regulation in human solid paediatric tumours
• Grantee: Mariana Camargo Maschietto
• Support type: Scholarships in Brazil - Young Researchers
• FAPESP's process: 12/50981-5 - High resolution genomic arrays and next generation sequencing in mental deficiency and congenital anomalies diagnosis
• Grantee: Francine Campagnari Guilhem
• Support type: Research Grants - Innovative Research in Small Business - PIPE