title: Peptidic degron in EID1 is recognized by an SCF E3 ligase complex containing the orphan F-box protein FBXO21.
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.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215;
authors.forename: Cuiyan
authors.initials: C
authors.lastname: Zhang
authors.affiliation: State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China;
authors.forename: Xiaotong
authors.initials: X
authors.lastname: Li
authors.affiliation: 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;
authors.forename: Guillaume
authors.initials: G
authors.lastname: Adelmant
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02215;
authors.forename: Jessica
authors.initials: J
authors.lastname: Dobbins
authors.affiliation: 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.
authors.forename: Christoph
authors.initials: C
authors.lastname: Geisen
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215;
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Oser
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02215;
authors.forename: Kai W
authors.initials: KW
authors.lastname: Wucherpfenning
authors.affiliation: 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;
authors.forename: Jarrod A
authors.initials: JA
authors.lastname: Marto
authors.affiliation: 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.
authors.forename: William G
authors.initials: WG
authors.lastname: Kaelin
mesh_terms: D000595:Amino Acid Sequence; D018797:Cell Cycle Proteins; D044783:F-Box Proteins / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D013058:Mass Spectrometry; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D025821:Polyubiquitin / Q000378:metabolism; D011485:Protein Binding; D059748:Proteolysis; D034741:RNA, Small Interfering / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry / Q000378:metabolism*; D015203:Reproducibility of Results; D016192:Resting Phase, Cell Cycle; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D018797:Cell Cycle Proteins; C416925:EID1 protein, human; D044783:F-Box Proteins; C000607216:FBXO21 protein, human; D009687:Nuclear Proteins; D010455:Peptides; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D025821:Polyubiquitin; D044843:SKP Cullin F-Box Protein Ligases
keywords: G0; cell cycle; degradation; pRB; ubiquitylation