Dataset Information

Cobalamins function as allosteric activators of an Angelman syndrome-associated UBE3A/E6AP variant

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 could be beneficial for AS individuals.

INSTRUMENT(S): Orbitrap Fusion, Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

DISEASE(S): Angelman Syndrome

SUBMITTER: Florian Stengel

LAB HEAD: Prof. Dr. Florian Stengel

PROVIDER: PXD048963 | Pride | 2024-05-09

REPOSITORIES: Pride

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			Action	DRS
	Data_referring_to_Table_S10.xlsx	Xlsx
	Data_referring_to_Table_S2.xlsx	Xlsx
	Data_referring_to_Table_S3.xlsx	Xlsx
	Data_referring_to_Table_S4.xlsx	Xlsx
	Data_referring_to_Table_S8.xlsx	Xlsx

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Publications

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

Müller Franziska F Jansen Jasmin J Offensperger Fabian F Eichbichler Daniela D Stengel Florian F Scheffner Martin M

Chembiochem : a European journal of chemical biology 20240502 10

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 ...[more]

PMID: 38573110

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