Cobalamins Function as Allosteric Activators of an Angelman Syndrome‐Associated UBE3A/E6AP Variant

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Abstract: Genetic aberrations of the maternal UBE3A allele, which encodes the E3 ubiquitin ligase E6AP, are the cause of Angelman syndrome (AS), an imprinting disorder. In most cases, the maternal UBE3A allele is not expressed. Yet, approximately 10 percent of AS individuals harbor distinct point mutations in the maternal allele resulting in the expression of full‐length E6AP variants that frequently display compromised ligase activity. In a high‐throughput screen, we identified cyanocobalamin, a vitamin B12‐derivative, and several alloxazine derivatives as activators of the AS‐linked E6AP‐F583S variant. Furthermore, we show by cross‐linking coupled to mass spectrometry that cobalamins affect the structural dynamics of E6AP‐F583S and apply limited proteolysis coupled to mass spectrometry to obtain information about the regions of E6AP that are involved in, or are affected by binding cobalamins and alloxazine derivatives. Our data suggest that dietary supplementation with vitamin B12 can be beneficial for AS individuals.

Location: Deutsche Nationalbibliothek Frankfurt am Main

Extent: Online-Ressource

Language: Englisch

Bibliographic citation: Cobalamins Function as Allosteric Activators of an Angelman Syndrome‐Associated UBE3A/E6AP Variant ; day:02 ; month:05 ; year:2024 ; extent:7
ChemBioChem ; (02.05.2024) (gesamt 7)

Creator: Müller, Franziska
Jansen, Jasmin
Offensperger, Fabian
Eichbichler, Daniela
Stengel, Florian
Scheffner, Martin

DOI: 10.1002/cbic.202400184

URN: urn:nbn:de:101:1-2405031405186.548104325605

Rights: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.

Last update: 14.08.2025, 10:50 AM CEST

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Müller, Franziska
Jansen, Jasmin
Offensperger, Fabian
Eichbichler, Daniela
Stengel, Florian
Scheffner, Martin

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