7SOL

Crystal Structures of the bispecific ubiquitin/FAT10 activating enzyme, Uba6

Summary for 7SOL

• Entry DOI: 10.2210/pdb7sol/pdb
• Descriptor: Ubiquitin-like modifier-activating enzyme 6, Ubiquitin, INOSITOL HEXAKISPHOSPHATE, ... (5 entities in total)
• Functional Keywords: ubiquitin, e1, adenylation, thioester bond, e2, fat10, ip6, ligase, atp-binding, nucleotide binding, conformational change, signaling protein, signaling protein-ligase complex, signaling protein/ligase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 250260.69

Authors

Olsen, S.K.,Gao, F.,Lv, Z. (deposition date: 2021-10-31, release date: 2022-11-02, Last modification date: 2024-10-23)

Primary citation

Yuan, L.,Gao, F.,Lv, Z.,Nayak, D.,Nayak, A.,Santos Bury, P.D.,Cano, K.E.,Jia, L.,Oleinik, N.,Atilgan, F.C.,Ogretmen, B.,Williams, K.M.,Davies, C.,El Oualid, F.,Wasmuth, E.V.,Olsen, S.K.
Crystal structures reveal catalytic and regulatory mechanisms of the dual-specificity ubiquitin/FAT10 E1 enzyme Uba6.
Nat Commun, 13:4880-4880, 2022

PubMed Abstract: The E1 enzyme Uba6 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. To gain mechanistic insights into these processes, we determined the crystal structure of a human Uba6/ubiquitin complex. Two distinct architectures of the complex are 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, an inositol hexakisphosphate (InsP6) molecule binds to a previously unidentified allosteric site on Uba6. Our structural, biochemical, and biophysical data indicate that InsP6 allosterically inhibits Uba6 activity by altering interconversion of the open and closed conformations of Uba6 while also enhancing its stability. In addition to revealing the molecular mechanisms of catalysis by Uba6 and allosteric regulation of its activities, our structures provide a framework for developing Uba6-specific inhibitors and raise the possibility of allosteric regulation of other E1s by naturally occurring cellular metabolites.

PubMed: 35986001
DOI: 10.1038/s41467-022-32613-5

Experimental method

X-RAY DIFFRACTION (2.25000635563 Å)