Not just a backup – UBA6 Dual Privacy

Image: UBA6 structure (surface representation colored according to domain geometry, active site cysteine ​​in pink) in complex with FAT10 (bar outline in yellow with surface representation in grid). Credit: Schindelin . Group

Researchers at the Rudolf Virchow Center at the University of Würzburg have revealed the crystal structures of UBA6 complexed with ATP or the ubiquitin-like protein FAT10. These results provide the basis for studying the individual roles of UBA6 toward ubiquitin or FAT10 binding to target proteins and downstream cellular pathways with potential etiological implications for some tumors. This study was published in the journal Nature Connections.

The ubiquitylation of target proteins is one of the most important post-translational modifications and plays essential roles in many of them cellular processes. The ubiquitin upregulation is performed by a sequential enzymatic cascade of E1-activating enzymes, E2-conjugated enzymes and E3-binding enzymes. For many years, UBA1 was thought to be the only E1 enzyme that activates ubiquitinUntil 2007, a second ubiquitin activating enzyme was discovered: UBA6.

A potential target for drug development

UBA6 is only found in vertebrates and sea urchins. Of interest, UBA6 is an unusual E1 enzyme in that it activates both ubiquitin and the ubiquitin-like protein (Ubl) FAT10. Due to its limited range of ubiquitinated events, compared to the general action of ubiquitin that activates the enzyme UBA1, and being the only E1-inducible attachment of FAT10, UBA6 is a potential drug target. To further explore the targeted inhibition of UAB6, it is necessary to understand its dual specificity and to identify variants enzyme which are impaired in the activation of ubiquitin or FAT10.

The research group of Professor Hermann Schindlin at the Rudolf Virchow Center at the University of Würzburg has reported the first structures of UBA6, in complex with ATP or FAT10. Interestingly, their structural and modeling studies also revealed how UBA6 allows dual recognition of ubiquitin and FAT10. Another key finding is the identification of UBA6 variants that selectively abrogate activation of either ubiquitin or FAT10. “These findings provide the basis for studying the individual roles that UBA6 plays in the activation of either ubiquitin or FAT10 in downstream cellular pathways,” Schindlin says.

intertwined in different diseases

As ubiquitination and FAT10ylation are involved in multiple cellular processes, it is not surprising that malfunctions in one or more components of this system can lead to a variety of diseases. UBA6-mediated proteasome degradation has been reported in brain-associated physiological and pathophysiological states in mice. Interestingly, UBA6 has been found to be overexpressed in the brains of humans from Alzheimer’s patients. The tumor suppressor protein p53 is a FAT10 substrate and dual negative regulation of FAT10 and p53 has been observed to be important in controlling tumorigenesis, which is consistent with the overexpression of FAT10 in many types of cancer cells.

While predictions regarding the orientation of ubiquitin in complex with UBA6 could be easily generated on the basis of the UBA6-ATP complex structure and the available UBA1-Ub structures, it seemed impossible to predict how FAT10 and, in particular, its N-terminal domain (NTD) interact with UBA6. Hence, identification of the UBA6-FAT10 co-crystal structure was a critical step. Based on experimentally derived structures and a model of the UBA6-ubiquitin complex, a selective switch was identified that led to the subsequent discovery of UBA6 variants that selectively abolished the activation of any modifier.

Future studies of UBA6 with selectively dysfunctional mutations are needed to investigate possible links between UBA6-stimulated ubiquitylation and FAT10ylation in the context of cancer. “If causal relationships can be established, targeted inhibition of UBA6 would be performed by enzymatic and in silico screening methods,” Schindlin explains. “With a group of mutants that selectively impair ubiquitination or FAT10ylation, we will investigate the selective impairment of either process in cell-based experiments with a particular focus on cancer cells.”

The team successfully analyzed the structure of the FAT10 protein toward a potential cancer treatment

more information:
Ngoc Truongvan et al, UBA6 structures explain its dual specificity for ubiquitin and FAT10, Nature Connections (2022). DOI: 10.1038 / s41467-022-32040-6

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