Crystal structures reveal catalytic and regulatory mechanisms of the dual-specificity ubiquitin/FAT10 E1 enzyme Uba6

Lingmin Yuan, Fei Gao, Zongyang Lv, Digant Nayak, Anindita Nayak, Priscila dos Santos Bury, Kristin E. Cano, Lijia Jia, Natalia Oleinik, Firdevs Cansu Atilgan, Besim Ogretmen, Katelyn M. Williams, Christopher Davies, Farid El Oualid, Elizabeth V. Wasmuth and Shaun K. Olsen ()
Additional contact information
Lingmin Yuan: University of Texas Health Science Center at San Antonio
Fei Gao: University of Texas Health Science Center at San Antonio
Zongyang Lv: University of Texas Health Science Center at San Antonio
Digant Nayak: University of Texas Health Science Center at San Antonio
Anindita Nayak: University of Texas Health Science Center at San Antonio
Priscila dos Santos Bury: University of Texas Health Science Center at San Antonio
Kristin E. Cano: University of Texas Health Science Center at San Antonio
Lijia Jia: University of Texas Health Science Center at San Antonio
Natalia Oleinik: Medical University of South Carolina
Firdevs Cansu Atilgan: Medical University of South Carolina
Besim Ogretmen: Medical University of South Carolina
Katelyn M. Williams: Johns Hopkins University School of Medicine
Christopher Davies: University of South Alabama
Farid El Oualid: UbiQ Bio B.V.
Elizabeth V. Wasmuth: University of Texas Health Science Center at San Antonio
Shaun K. Olsen: University of Texas Health Science Center at San Antonio

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: 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.

Date: 2022
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-022-32613-5 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32613-5

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-022-32613-5

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().