Mechanistic insights revealed by a UBE2A mutation linked to intellectual disability
| Autor: | Juliana Ferreira de Oliveira, Camila Canateli, Carla Rosenberg, Paulo Alberto Otto, Ana Cristina Victorino Krepischi, Rachel E. Klevit, Mariana Maschietto, Americo Tavares Ranzani, Paulo S. Oliveira, Kleber G. Franchini, Silvia S. Costa, Paula Favoretti Vital do Prado, Maurício L. Sforça |
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| Přispěvatelé: | UNIVERSIDADE ESTADUAL DE CAMPINAS |
| Rok vydání: | 2018 |
| Předmět: |
Adult
Male Magnetic Resonance Spectroscopy Lysine Mutation Missense Intellectual disability Crystallography X-Ray medicine.disease_cause 03 medical and health sciences Ubiquitin Catalytic Domain Intellectual Disability Proliferating Cell Nuclear Antigen medicine Humans Artigo original Missense mutation Deficiência intelectual Ubiquitins Molecular Biology 030304 developmental biology chemistry.chemical_classification 0303 health sciences DNA ligase Mutation biology Chemistry 030302 biochemistry & molecular biology Ubiquitination Cell Biology Hydrogen-Ion Concentration Ubiquitina PESSOAS COM DEFICIÊNCIA INTELECTUAL Protein ubiquitination Ubiquitin ligase Biochemistry Ubiquitin-Conjugating Enzymes biology.protein Female Cysteine |
| Zdroj: | Repositório da Produção Científica e Intelectual da Unicamp Universidade Estadual de Campinas (UNICAMP) instacron:UNICAMP Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP |
| ISSN: | 1552-4469 1552-4450 |
| Popis: | Agradecimentos: LNBio/CNPEM; Brazilian National Council for Scientific and Technological Development (CNPq)National Council for Scientific and Technological Development (CNPq) [306879/2014-0, 310536/2014-6, 422790/2016-8]; Sao Paulo Research Foundation (FAPESP)Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2012/50981-5, 2013/08028-1, 2015/06281-7]; NIH/NIGMSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of General Medical Sciences (NIGMS) [R01 GM088055] 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 FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQ Fechado |
| Databáze: | OpenAIRE |
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