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Proc Natl Acad Sci U S A. 2015 Dec 15;112(50):15372-7. doi: 10.1073/pnas.1522006112. Epub 2015 Dec 2.

Peptidic degron in EID1 is recognized by an SCF E3 ligase complex containing the orphan F-box protein FBXO21.

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215;
2
State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China;
3
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215; Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, MA 02215; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02215;
4
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02215;
5
Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215; Howard Hughes Medical Institute, Chevy Chase, MD 20815.
6
Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215; Howard Hughes Medical Institute, Chevy Chase, MD 20815 william_kaelin@dfci.harvard.edu.

Abstract

EP300-interacting inhibitor of differentiation 1 (EID1) belongs to a protein family implicated in the control of transcription, differentiation, DNA repair, and chromosomal maintenance. EID1 has a very short half-life, especially in G0 cells. We discovered that EID1 contains a peptidic, modular degron that is necessary and sufficient for its polyubiquitylation and proteasomal degradation. We found that this degron is recognized by an Skp1, Cullin, and F-box (SCF)-containing ubiquitin ligase complex that uses the F-box Only Protein 21 (FBXO21) as its substrate recognition subunit. SCF(FBXO21) polyubiquitylates EID1 both in vitro and in vivo and is required for the efficient degradation of EID1 in both cycling and quiescent cells. The EID1 degron partially overlaps with its retinoblastoma tumor suppressor protein-binding domain and is congruent with a previously defined melanoma-associated antigen-binding motif shared by EID family members, suggesting that binding to retinoblastoma tumor suppressor and melanoma-associated antigen family proteins could affect the polyubiquitylation and turnover of EID family members in cells.

KEYWORDS:

G0; cell cycle; degradation; pRB; ubiquitylation

PMID:
26631746
PMCID:
PMC4687553
DOI:
10.1073/pnas.1522006112
[Indexed for MEDLINE]
Free PMC Article

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