Domain alternation and active site remodeling are conserved structural features of ubiquitin E1

Lv, Zongyang; Yuan, Lingmin; Atkison, James H.; Aldana-Masangkay, Grace; Chen, Yuan; Olsen, Shaun K.

doi:10.1074/jbc.m117.787622

Domain alternation and active site remodeling are conserved structural features of ubiquitin E1

Journal Article · Thu Jun 01 04:00:00 EDT 2017 · Journal of Biological Chemistry

DOI:https://doi.org/10.1074/jbc.m117.787622· OSTI ID:1376240

Lv, Zongyang ^[1]; Yuan, Lingmin ^[1]; Atkison, James H. ^[1]; Aldana-Masangkay, Grace ^[2]; Chen, Yuan ^[2]; Olsen, Shaun K. ^[1]

Medical Univ. of South Carolina, Charleston, SC (United States). Dept. of Biochemistry and Molecular Biology. Hollings Cancer Center
Beckman Research Inst. of City of Hope, Duarte, CA (United States). Dept. of Molecular Medicine

E1 enzymes for ubiquitin (Ub) and Ub-like modifiers (Ubls) harbor two catalytic activities that are required for Ub/Ubl activation: adenylation and thioester bond formation. Structural studies of the E1 for the Ubl small ubiquitin-like modifier (SUMO) revealed a single active site that is transformed by a conformational switch that toggles its competency for catalysis of these two distinct chemical reactions. Although the mechanisms of adenylation and thioester bond formation revealed by SUMO E1 structures are thought to be conserved in Ub E1, there is currently a lack of structural data supporting this hypothesis. Here, we present a structure of Schizosaccharomyces pombe Uba1 in which the second catalytic cysteine half-domain (SCCH domain) harboring the catalytic cysteine has undergone a 106° rotation that results in a completely different network of intramolecular interactions between the SCCH and adenylation domains and translocation of the catalytic cysteine 12 Å closer to the Ub C terminus compared with previous Uba1 structures. SCCH domain alternation is accompanied by conformational changes within the Uba1 adenylation domains that effectively disassemble the adenylation active site. Importantly, the structural and biochemical data suggest that domain alternation and remodeling of the adenylation active site are interconnected and are intrinsic structural features of Uba1 and that the overall structural basis for adenylation and thioester bond formation exhibited by SUMO E1 is indeed conserved in Ub E1. Finally, the mechanistic insights provided by the novel conformational snapshot of Uba1 presented in this study may guide efforts to develop small molecule inhibitors of this critically important enzyme that is an active target for anticancer therapeutics.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1376240

Journal Information:: Journal of Biological Chemistry, Journal Name: Journal of Biological Chemistry Journal Issue: 29 Vol. 292; ISSN 0021-9258

Publisher:: American Society for Biochemistry and Molecular BiologyCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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59 BASIC BIOLOGICAL SCIENCES
E1
X-ray crystallography
adenylation
conformational change
domain alternation
enzyme mechanism
enzyme structure
structure-function
thioester
ubiquitin

Domain alternation and active site remodeling are conserved structural features of ubiquitin E1

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References (30)

Cited By (4)

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