UBE3A Mutation Prevents Enzyme From Binding to Proteasome, Contributing to Angelman Symptoms, Study Finds

Joana Carvalho, PhD avatar

by Joana Carvalho, PhD |

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Coffin-Siris syndrome, mutation, Angelman

Researchers from Harvard Medical School have discovered that a genetic mutation in the UBE3A gene found in Angelman syndrome patients prevents an enzyme called ubiquitin ligase E3A from interacting with one of its major binding partners, the proteasome, contributing to disease symptoms.

The study, “Angelman syndrome-associated point mutations in the Zn-binding N-terminal (AZUL) domain of UBE3A ubiquitin ligase inhibit binding to the proteasome,” was published in the Journal of Biological Chemistry.

Angelman syndrome is a genetic neurological disorder caused by the loss or malfunction of the maternal copy of the UBE3A gene — which provides instructions for making an enzyme called ubiquitin protein ligase E3A that normally targets other proteins to be destroyed at the proteasome.

The proteasome is a complex of enzymes responsible for the destruction of unneeded or damaged proteins.

Previous studies had already revealed that ubiquitin protein ligase interacts with the 26S proteasome — a large protein complex that serves as the degrading arm of the ubiquitin system.

However, the impact of these interactions between ubiquitin ligase and the proteasome in normal conditions and in the context of disease are not yet fully understood.

In this study, researchers characterized the interaction between ubiquitin protein ligase and the proteasome, using biochemical assays and different cell lines cultured in a lab dish.

Results revealed that the ubiquitin protein ligase interacts with the proteasome’s PSMD4 (Rpn10/S5a) subunit through a specific region of the protein that is highly conserved in different animal species, called the AZUL (amino-terminal zinc-finger of UBE3A ligase) domain.

Interestingly, two different point mutations (single nucleotide mutations that may change protein composition) linked to Angelman syndrome (G20V and C21Y) that affect the structure of the AZUL domain also prevented ubiquitin protein ligase from binding to PSMD4.

This indicated that the AZUL domain must remain intact for this physical interaction to occur.

Although these mutations in the AZUL domain did not compromise certain regulatory functions mediated by ubiquitin protein ligase, they prevented the protein from activating a specific cellular signaling cascade, called Wnt/β-Catenin, that is involved in several processes, including the development of nerve cells.

These findings suggest that disrupting the binding of ubiquitin protein ligase to the proteasome and the subsequent deregulation of Wnt/β-Catenin signaling might contribute to the symptoms experienced by patients with Angelman syndrome.

“This is the first report that a mutation found in AS [Angelman syndrome] patients affects the interaction of UBE3A with one of its major binding partners. Our findings suggest that the impairment of those mutants to bind to the proteasome and activate the Wnt/β-Catenin signaling pathway may contribute to the symptoms observed in Angelman Syndrome,” the researchers wrote.

“This also highlights the possibility that different UBE3A mutations affecting different functions of UBE3A (i.e. proteasome binding and ubiquitin ligase activity) might result in comparable physiological or pathological outcomes,” they concluded.