6cyo

Publication Abstract from PubMed

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 low-pKa 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.

Mechanistic insights revealed by a UBE2A mutation linked to intellectual disability.,de Oliveira JF, do Prado PFV, da Costa SS, Sforca ML, Canateli C, Ranzani AT, Maschietto M, de Oliveira PSL, Otto PA, Klevit RE, Krepischi ACV, Rosenberg C, Franchini KG Nat Chem Biol. 2019 Jan;15(1):62-70. doi: 10.1038/s41589-018-0177-2. Epub 2018, Dec 10. PMID:30531907^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.