Review
Activating the ubiquitin family: UBA6 challenges the field

https://doi.org/10.1016/j.tibs.2008.01.005Get rights and content

Since its discovery in 1981, ubiquitin-activating enzyme 1 was thought to be the only E1-type enzyme responsible for ubiquitin activation. Recently, a relatively uncharacterized E1 enzyme, designated ubiquitin-like modifier activating enzyme 6, was also shown to activate ubiquitin. Ubiquitin-activating enzyme 1 and ubiquitin-like modifier activating enzyme 6 are both essential proteins, and each uses a different spectrum of ubiquitin-conjugating (E2) enzymes. Ubiquitin-like modifier activating enzyme 6 activates not only ubiquitin, but also the ubiquitin-like modifier FAT10 (human leukocyte antigen F-associated transcript 10), which, similarly to ubiquitin, serves as a signal for proteasomal degradation. This new layer of regulation in ubiquitin activation markedly increases the versatility of the ubiquitin conjugation system.

Section snippets

The ubiquitin family

The post-translational modification of proteins by phosphate, sugars or lipids has long been recognized as a means to alter the properties of proteins. When the ATP-dependent degradation of proteins was first investigated nearly three decades ago, it became clear that the scope of protein modifications extends to the covalent linkage with a 76-residue polypeptide termed ubiquitin 1, 2. The ubiquitin C terminus becomes isopeptide-linked to the ɛ-amino group of lysines within target proteins.

Structure and enzymatic mechanisms of E1 enzymes

To date, eight E1 enzymes have been identified owing to their conserved three-domain structure, and most have been assigned to one of the known ULMs (Table 1). E1 enzymes are either formed by a single polypeptide chain or are heterodimers such as the E1 enzymes AOS1–UBA2 and β-amyloid precursor protein-binding protein (APP-BP)-1–UBA3 for SUMO1–3 and NEDD8, respectively, which carry the characteristic E1 domains on two separate polypeptides 18, 19. One task of E1 enzymes is to bind noncovalently

UBA6: a second ubiquitin-activating enzyme

An E1 enzyme that activates ubiquitin was initially described, characterized and purified in 1981 and 1982 20, 28, 29; corresponding genes, named UBA1 in yeast and plants and UBE1 in mammals, were cloned a decade later 30, 31, 32, 33. In Saccharomyces cerevisiae, UBA1 is essential, indicating that no other E1-type enzyme can compensate for this deficiency. In mammals, UBE1 is encoded on the X chromosome, which explains how mutations in the single copy of UBE1 generated several

UBA6 activates two different modifiers: ubiquitin and FAT10

UBA6 challenges a second major paradigm in the ubiquitin field – namely, that a specific E1 enzyme only activates one type or one closely related subfamily of modifiers. Thoroughly investigated examples for this selectivity are NEDD8 and ubiquitin, which are nearly 60% identical; a single arginine residue in the E1 for NEDD8 determines its selectivity for NEDD8 and prevents aberrant ubiquitin activation [46]. By contrast, UBA6 was recently shown to activate two ubiquitin family proteins,

Concluding remarks and future perspectives

The unique properties of UBA6 challenge two major paradigms of ULM conjugation: first, UBE1 and UBA6 are the first examples of E1 enzymes that both activate the same member of the ULM family, and, second, UBA6 is, aside from ATG7 and AOS1–UBA2, the third example of an E1 that activates two ULMs: ubiquitin and FAT10, which have widely different structural and biological properties. Because UBE1 and UBA6 cooperate with only partially overlapping pools of E2 enzymes 16, 17, it is expected that at

Acknowledgements

We thank Ingrid Kassner for critical reading of the manuscript, and Qiong Tong, Kay Diederichs and Stefanie Fischer for their help with figure preparation. Work in our laboratories was supported by the German Research Foundation (grant GR 1517/2–3) and the Fritz Thyssen Foundation (grant Az. 10.05.1.145).

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