UBE2S Drives Elongation of K11-linked Ubiquitin Chains by the Anaphase-promoting Complex

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2010 Jan 19

PMID 20080579

Citations 140

Authors

Tao Wu

Yifat Merbl

Ying Huo

Jennifer L Gallop

Amit Tzur

Marc W Kirschner

Affiliations

Soon will be listed here.

Abstract

The Anaphase-Promoting Complex (APC) is an E3 ubiquitin ligase that regulates mitosis and G1 by sequentially targeting cell-cycle regulators for ubiquitination and proteasomal degradation. The mechanism of ubiquitin chain formation by APC and the resultant chain topology remains controversial. By using a single-lysine APC substrate to dissect the topology of ubiquitinated substrates, we find that APC-catalyzed ubiquitination has an intrinsic preference for the K11 linkage of ubiquitin that is essential for substrate degradation. K11 specificity is determined by an E2 enzyme, UBE2S/E2-EPF, that elongates ubiquitin chains after the substrates are pre-ubiquitinated by UbcH10 or UbcH5. UBE2S copurifies with APC; dominant-negative Ube2S slows down APC substrate degradation in functional cell-cycle extracts. We propose that Ube2S is a critical, unique component of the APC ubiquitination pathway.

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References

Garnett M, Mansfeld J, Godwin C, Matsusaka T, Wu J, Russell P . UBE2S elongates ubiquitin chains on APC/C substrates to promote mitotic exit. Nat Cell Biol. 2009; 11(11):1363-9. PMC: 2875106. DOI: 10.1038/ncb1983. View

Zou H, McGarry T, Bernal T, Kirschner M . Identification of a vertebrate sister-chromatid separation inhibitor involved in transformation and tumorigenesis. Science. 1999; 285(5426):418-22. DOI: 10.1126/science.285.5426.418. View

Reddy S, Rape M, Margansky W, Kirschner M . Ubiquitination by the anaphase-promoting complex drives spindle checkpoint inactivation. Nature. 2007; 446(7138):921-5. DOI: 10.1038/nature05734. View

Ikeda F, Dikic I . Atypical ubiquitin chains: new molecular signals. 'Protein Modifications: Beyond the Usual Suspects' review series. EMBO Rep. 2008; 9(6):536-42. PMC: 2427391. DOI: 10.1038/embor.2008.93. View

Peng J, Schwartz D, Elias J, Thoreen C, Cheng D, Marsischky G . A proteomics approach to understanding protein ubiquitination. Nat Biotechnol. 2003; 21(8):921-6. DOI: 10.1038/nbt849. View

Tedesco D, Zhang J, Trinh L, Lalehzadeh G, Meisner R, Yamaguchi K . The ubiquitin-conjugating enzyme E2-EPF is overexpressed in primary breast cancer and modulates sensitivity to topoisomerase II inhibition. Neoplasia. 2007; 9(7):601-13. PMC: 1939933. DOI: 10.1593/neo.07385. View

Rodrigo-Brenni M, Morgan D . Sequential E2s drive polyubiquitin chain assembly on APC targets. Cell. 2007; 130(1):127-39. DOI: 10.1016/j.cell.2007.05.027. View

Thrower J, Hoffman L, Rechsteiner M, Pickart C . Recognition of the polyubiquitin proteolytic signal. EMBO J. 2000; 19(1):94-102. PMC: 1171781. DOI: 10.1093/emboj/19.1.94. View

Bennett E, Shaler T, Woodman B, Ryu K, Zaitseva T, Becker C . Global changes to the ubiquitin system in Huntington's disease. Nature. 2007; 448(7154):704-8. DOI: 10.1038/nature06022. View

10.

Christensen D, Brzovic P, Klevit R . E2-BRCA1 RING interactions dictate synthesis of mono- or specific polyubiquitin chain linkages. Nat Struct Mol Biol. 2007; 14(10):941-8. DOI: 10.1038/nsmb1295. View

11.

Liu Z, Diaz L, Haas A, Giudice G . cDNA cloning of a novel human ubiquitin carrier protein. An antigenic domain specifically recognized by endemic pemphigus foliaceus autoantibodies is encoded in a secondary reading frame of this human epidermal transcript. J Biol Chem. 1992; 267(22):15829-35. View

12.

Baboshina O, Haas A . Novel multiubiquitin chain linkages catalyzed by the conjugating enzymes E2EPF and RAD6 are recognized by 26 S proteasome subunit 5. J Biol Chem. 1996; 271(5):2823-31. DOI: 10.1074/jbc.271.5.2823. View

13.

Pickart C, Fushman D . Polyubiquitin chains: polymeric protein signals. Curr Opin Chem Biol. 2004; 8(6):610-6. DOI: 10.1016/j.cbpa.2004.09.009. View

14.

Yu H, King R, Peters J, Kirschner M . Identification of a novel ubiquitin-conjugating enzyme involved in mitotic cyclin degradation. Curr Biol. 1996; 6(4):455-66. DOI: 10.1016/s0960-9822(02)00513-4. View

15.

Rape M, Reddy S, Kirschner M . The processivity of multiubiquitination by the APC determines the order of substrate degradation. Cell. 2006; 124(1):89-103. DOI: 10.1016/j.cell.2005.10.032. View

16.

Aristarkhov A, Eytan E, Moghe A, Admon A, Hershko A, Ruderman J . E2-C, a cyclin-selective ubiquitin carrier protein required for the destruction of mitotic cyclins. Proc Natl Acad Sci U S A. 1996; 93(9):4294-9. PMC: 39529. DOI: 10.1073/pnas.93.9.4294. View

17.

King R, Glotzer M, Kirschner M . Mutagenic analysis of the destruction signal of mitotic cyclins and structural characterization of ubiquitinated intermediates. Mol Biol Cell. 1996; 7(9):1343-57. PMC: 275986. DOI: 10.1091/mbc.7.9.1343. View

18.

Liu Z, Haas A, Diaz L, Conrad C, Giudice G . Characterization of a novel keratinocyte ubiquitin carrier protein. J Biol Chem. 1996; 271(5):2817-22. DOI: 10.1074/jbc.271.5.2817. View

19.

Windheim M, Peggie M, Cohen P . Two different classes of E2 ubiquitin-conjugating enzymes are required for the mono-ubiquitination of proteins and elongation by polyubiquitin chains with a specific topology. Biochem J. 2007; 409(3):723-9. DOI: 10.1042/BJ20071338. View

20.

Kirkpatrick D, Hathaway N, Hanna J, Elsasser S, Rush J, Finley D . Quantitative analysis of in vitro ubiquitinated cyclin B1 reveals complex chain topology. Nat Cell Biol. 2006; 8(7):700-10. DOI: 10.1038/ncb1436. View