Mechanistic insights revealed by a UBE2A mutation linked to intellectual disability.
Adult
Catalytic Domain
Crystallography, X-Ray
Female
Humans
Hydrogen-Ion Concentration
Intellectual Disability
/ genetics
Lysine
/ metabolism
Magnetic Resonance Spectroscopy
Male
Mutation, Missense
Proliferating Cell Nuclear Antigen
/ metabolism
Ubiquitin
/ chemistry
Ubiquitin-Conjugating Enzymes
/ chemistry
Ubiquitination
Journal
Nature chemical biology
ISSN: 1552-4469
Titre abrégé: Nat Chem Biol
Pays: United States
ID NLM: 101231976
Informations de publication
Date de publication:
01 2019
01 2019
Historique:
received:
10
04
2018
accepted:
26
10
2018
entrez:
12
12
2018
pubmed:
12
12
2018
medline:
9
5
2019
Statut:
ppublish
Résumé
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
Identifiants
pubmed: 30531907
doi: 10.1038/s41589-018-0177-2
pii: 10.1038/s41589-018-0177-2
pmc: PMC6626659
mid: NIHMS1031040
doi:
Substances chimiques
PCNA protein, human
0
Proliferating Cell Nuclear Antigen
0
Ubiquitin
0
UBE2A protein, human
EC 2.3.2.23
Ubiquitin-Conjugating Enzymes
EC 2.3.2.23
Lysine
K3Z4F929H6
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
62-70Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM088055
Pays : United States
Commentaires et corrections
Type : CommentIn
Références
Annu Rev Biochem. 2001;70:503-33
pubmed: 11395416
J Biol Chem. 2002 Jun 14;277(24):21913-21
pubmed: 11927573
Nature. 2002 Sep 12;419(6903):135-41
pubmed: 12226657
Biophys J. 2002 Oct;83(4):1731-48
pubmed: 12324397
Mol Cell. 2006 Mar 17;21(6):873-80
pubmed: 16543155
Nat Struct Mol Biol. 2006 Jun;13(6):491-9
pubmed: 16732283
Am J Hum Genet. 2006 Sep;79(3):549-55
pubmed: 16909393
Nat Struct Mol Biol. 2006 Oct;13(10):915-20
pubmed: 16980971
Nature. 2007 Mar 15;446(7133):333-7
pubmed: 17310145
J Androl. 2008 Sep-Oct;29(5):564-71
pubmed: 18497339
FASEB J. 2010 Apr;24(4):981-93
pubmed: 19940261
Proteins. 2010 Apr;78(5):1291-301
pubmed: 20014027
Structure. 2010 Jan 13;18(1):138-47
pubmed: 20152160
J Hum Genet. 2010 Apr;55(4):244-7
pubmed: 20339384
Clin Genet. 2010 Jun;77(6):541-51
pubmed: 20412111
Am J Med Genet A. 2010 Dec;152A(12):3084-90
pubmed: 21108393
Biochemistry. 2011 Mar 15;50(10):1624-33
pubmed: 21226485
Cell. 2011 Mar 4;144(5):769-81
pubmed: 21376237
Proc Natl Acad Sci U S A. 2011 Apr 5;108(14):5590-5
pubmed: 21422291
Mol Cell. 2011 Apr 8;42(1):75-83
pubmed: 21474069
Annu Rev Biochem. 2012;81:203-29
pubmed: 22524316
Biochemistry. 2012 May 22;51(20):4175-87
pubmed: 22551455
Nature. 2012 Sep 6;489(7414):115-20
pubmed: 22842904
Mol Cell. 2012 Sep 28;47(6):933-42
pubmed: 22885007
Mol Cancer Ther. 2013 Apr;12(4):373-83
pubmed: 23339190
Mol Cell. 2013 Jun 27;50(6):831-43
pubmed: 23685073
Orphanet J Rare Dis. 2013 Sep 21;8:146
pubmed: 24053514
Eur J Hum Genet. 2014 Jun;22(6):792-800
pubmed: 24253858
Eur J Paediatr Neurol. 2014 May;18(3):327-37
pubmed: 24508361
Transl Oncol. 2014 May 12;:null
pubmed: 24831578
PLoS One. 2014 Jul 08;9(7):e101663
pubmed: 25003393
Am J Med Genet A. 2015 Jan;167A(1):204-10
pubmed: 25287747
Nat Med. 2014 Nov;20(11):1242-53
pubmed: 25375928
Mol Cell Proteomics. 2015 Mar;14(3):674-85
pubmed: 25582440
Eur J Hum Genet. 2015 Nov;23(11):1513-8
pubmed: 25649377
PLoS One. 2015 Feb 13;10(2):e0116454
pubmed: 25679214
Nat Struct Mol Biol. 2015 Aug;22(8):597-602
pubmed: 26148049
Nucleic Acids Res. 2015 Oct 15;43(18):9039-50
pubmed: 26286193
Sci Rep. 2015 Nov 23;5:16793
pubmed: 26592444
Biochem Biophys Res Commun. 2016 Jan 15;469(3):449-55
pubmed: 26679603
Cell Res. 2016 Apr;26(4):423-40
pubmed: 27002219
J Neurochem. 2016 Dec;139(6):1081-1092
pubmed: 27365114
Chem Rev. 2018 Feb 14;118(3):889-918
pubmed: 28234446
Hum Genome Var. 2017 Jun 08;4:17019
pubmed: 28611923
J Mol Biol. 2017 Nov 10;429(22):3430-3440
pubmed: 28625848
Am J Med Genet A. 2018 Jan;176(1):107-115
pubmed: 29159939
Am J Med Genet A. 2018 Mar;176(3):722-726
pubmed: 29283210
J Biol Chem. 1985 Feb 10;260(3):1573-81
pubmed: 2981864
Dev Biol. 1996 Jan 10;173(1):119-32
pubmed: 8575614