RING E3 mechanism for ubiquitin ligation to a disordered substrate visualized for human anaphase-promoting complex

Brown, Nicholas G.; VanderLinden, Ryan; Watson, Edmond R.; Qiao, Renping; Grace, Christy R. R.; Yamaguchi, Masaya; Weissmann, Florian; Frye, Jeremiah J.; Dube, Prakash; Ei Cho, Shein; Actis, Marcelo L.; Rodrigues, Patrick; Fujii, Naoaki; Peters, Jan-Michael; Stark, Holger; Schulman, Brenda A.

doi:10.1073/pnas.1504161112

RING E3 mechanism for ubiquitin ligation to a disordered substrate visualized for human anaphase-promoting complex

Journal Article · Mon Mar 30 00:00:00 EDT 2015 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.1504161112· OSTI ID:1197027

Brown, Nicholas G. ^[1]; VanderLinden, Ryan ^[2]; Watson, Edmond R. ^[3]; Qiao, Renping ^[4]; Grace, Christy R. R. ^[1]; Yamaguchi, Masaya ^[1]; Weissmann, Florian ^[4]; Frye, Jeremiah J. ^[1]; Dube, Prakash ^[5]; Ei Cho, Shein ^[1]; Actis, Marcelo L. ^[6]; Rodrigues, Patrick ^[7]; Fujii, Naoaki ^[6]; Peters, Jan-Michael ^[4]; Stark, Holger ^[5]; Schulman, Brenda A. ^[8]

St. Jude Children's Research Hospital, Memphis, TN (United States). Dept. of Structural Biology
St. Jude Children's Research Hospital, Memphis, TN (United States). Dept. of Structural Biology. Howard Hughes Medical Inst.
St. Jude Children's Research Hospital, Memphis, TN (United States). Dept. of Structural Biology; Univ. of Tennessee Health Sciences Center, Memphis, TN (United States). Dept. of Microbiology, Immunology, and Biochemistry
Vienna Biocenter (VBC) (Austria). Research Inst. of Molecular Pathology (IMP)
Max Planck Inst. for Biophysical Chemistry, Gottingen (Germany); Univ. of Gottingen (Germany). Dept. of 3D Electron Cryomicroscopy. Inst. of Microbiology and Genetics
St. Jude Children's Research Hospital, Memphis, TN (United States). Dept. of Chemical Biology and Therapeutics
St. Jude Children's Research Hospital, Memphis, TN (United States). Hartwell Center for Bioinformatics and Biotechnology
St. Jude Children's Research Hospital, Memphis, TN (United States). Dept. of Structural Biology. Howard Hughes Medical Inst.; Univ. of Tennessee Health Sciences Center, Memphis, TN (United States). Dept. of Microbiology, Immunology, and Biochemistry

For many E3 ligases, a mobile RING (Really Interesting New Gene) domain stimulates ubiquitin (Ub) transfer from a thioester-linked E2~Ub intermediate to a lysine on a remotely bound disordered substrate. One such E3 is the gigantic, multisubunit 1.2-MDa anaphase-promoting complex/cyclosome (APC), which controls cell division by ubiquitinating cell cycle regulators to drive their timely degradation. Intrinsically disordered substrates are typically recruited via their KEN-box, D-box, and/or other motifs binding to APC and a coactivator such as CDH1. On the opposite side of the APC, the dynamic catalytic core contains the cullin-like subunit APC2 and its RING partner APC11, which collaborates with the E2 UBCH10 (UBE2C) to ubiquitinate substrates. However, how dynamic RING–E2~Ub catalytic modules such as APC11–UBCH10~Ub collide with distally tethered disordered substrates remains poorly understood. In this paper, we report structural mechanisms of UBCH10 recruitment to APC^CDH1 and substrate ubiquitination. Unexpectedly, in addition to binding APC11’s RING, UBCH10 is corecruited via interactions with APC2, which we visualized in a trapped complex representing an APC^CDH1–UBCH10~Ub–substrate intermediate by cryo-electron microscopy, and in isolation by X-ray crystallography. To our knowledge, this is the first structural view of APC, or any cullin–RING E3, with E2 and substrate juxtaposed, and it reveals how tripartite cullin–RING–E2 interactions establish APC’s specificity for UBCH10 and harness a flexible catalytic module to drive ubiquitination of lysines within an accessible zone. Finally, we propose that multisite interactions reduce the degrees of freedom available to dynamic RING E3–E2~Ub catalytic modules, condense the search radius for target lysines, increase the chance of active-site collision with conformationally fluctuating substrates, and enable regulation.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Lab. (ANL), Argonne, IL (United States); Max Planck Inst. for Biophysical Chemistry, Gottingen (Germany); St. Jude Children's Research Hospital, Memphis, TN (United States); Univ. of Goettingen (Germany); Vienna Biocenter (VBC) (Austria)

Sponsoring Organization:: American Cancer Society (United States); American Lebanese Syrian Associated Charities (ALSAC) (United States); Austrian Research Fund (Austria); Boehringer Ingelheim (Germany); European Union (Belgium); German Research Foundation (DFG) (Germany); Howard Hughes Medical Inst. (United States); Jane Coffin Childs Foundation (United States); Japan Society for the Promotion of Science (Japan); Laura Bassi Centre for Optimized Structural Studies (Austria); National Inst. of Health (NIH) (United States); USDOE Office of Science (SC)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1197027

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Issue: 17 Vol. 112; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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