UbiQ is proud to have been part of a major collaborative research project focused on studying the dual-specificity ubiquitin/FAT10 E1 enzyme Uba6 and whose results have been published in Nature Communications 2022, 13, article 4880.

Abstract: Uba6 is an E1 enzyme that initiates signal transduction by activating ubiquitin and the ubiquitin-like protein FAT10 in a two-step process involving sequential catalysis of adenylation and thioester bond formation. By determining the crystal structure of a human Uba6-ubiquitin complex, two distinct architectures were observed: one in which Uba6 adopts an open conformation (with the active site configured for catalysis of adenylation), and a second drastically different closed conformation in which the adenylation active site is disassembled and reconfigured for catalysis of thioester bond formation. Surprisingly, one molecule of the important cellular metabolite inositol hexakisphosphate (InsP6) was found to bind a previously unidentified allosteric site on Uba6. Our data indicate that InsP6 binding not only enhances Uba6 stability but also inhibits its activity by altering interconversion of the open and closed conformation. Thus, in addition to revealing the molecular mechanisms of catalysis by Uba6 and allosteric regulation of its activities, our data* provide a framework for developing Uba6-specific inhibitors and raise the possibility of allosteric regulation of other E1s by naturally occurring cellular metabolites.

1. Department of Biochemistry & Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
2. Department of Research & Development, Beijing IPE Center for Clinical LaboratoryCO, Beijing 100176,China.
3. Department of Biochemistry & Molecular Biology and Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. 
4. Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
5. Department of Biochemistry & Molecular Biology, University of South Alabama, Mobile, AL 36688, USA.
6. UbiQ Bio B.V., Science Park 408, 1098 XH Amsterdam, The Netherlands.
7. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
8. These authors contributed equally: Lingmin Yuan and Fei Gao.

* Note: Schindelin and co-workers also recently reported the structures of Uba6 with FAT10 and ATP (Nature Communications 2022, 13, article 4789).