6CYR

Crystal structure of the UBE2A variant Q93E

Summary for 6CYR

• Entry DOI: 10.2210/pdb6cyr/pdb
• Related: 6CYO
• Descriptor: Ubiquitin-conjugating enzyme E2 A (2 entities in total)
• Functional Keywords: ubiquitin-conjungating enzyme e2 a, q93e variant, ligase, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 17615.63

Authors

Ranzani, A.T.,de Oliveira, J.F. (deposition date: 2018-04-06, release date: 2018-12-12, Last modification date: 2024-10-30)

Primary citation

de Oliveira, J.F.,do Prado, P.F.V.,da Costa, S.S.,Sforca, M.L.,Canateli, C.,Ranzani, A.T.,Maschietto, M.,de Oliveira, P.S.L.,Otto, P.A.,Klevit, R.E.,Krepischi, A.C.V.,Rosenberg, C.,Franchini, K.G.
Mechanistic insights revealed by a UBE2A mutation linked to intellectual disability.
Nat. Chem. Biol., 15:62-70, 2019

PubMed 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 low-pK 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.

PubMed: 30531907
DOI: 10.1038/s41589-018-0177-2

Experimental method

X-RAY DIFFRACTION (2.2 Å)