title: Dimer formation and conformational flexibility ensure cytoplasmic stability and nuclear accumulation of Elk-1.
abstract: The ETS (E26) protein Elk-1 serves as a paradigm for mitogen-responsive transcription factors. It is multiply phosphorylated by mitogen-activated protein kinases (MAPKs), which it recruits into pre-initiation complexes on target gene promoters. However, events preparatory to Elk-1 phosphorylation are less well understood. Here, we identify two novel, functional elements in Elk-1 that determine its stability and nuclear accumulation. One element corresponds to a dimerization interface in the ETS domain and the second is a cryptic degron adjacent to the serum response factor (SRF)-interaction domain that marks dimerization-defective Elk-1 for rapid degradation by the ubiquitin-proteasome system. Dimerization appears to be crucial for Elk-1 stability only in the cytoplasm, as latent Elk-1 accumulates in the nucleus and interacts dynamically with DNA as a monomer. These findings define a novel role for the ETS domain of Elk-1 and demonstrate that nuclear accumulation of Elk-1 involves conformational flexibility prior to its phosphorylation by MAPKs.
authors.affiliation: School of Biomedical Sciences, Queen's Medical Centre, Nottingham, NG7 2UH, UK.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Evans
authors.forename: Janice
authors.initials: J
authors.lastname: Saxton
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Shelton
authors.forename: Andreas
authors.initials: A
authors.lastname: Begitt
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Holliday
authors.forename: Robert A
authors.initials: RA
authors.lastname: Hipskind
authors.forename: Peter E
authors.initials: PE
authors.lastname: Shaw
mesh_terms: D000595:Amino Acid Sequence; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D019281:Dimerization; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011487:Protein Conformation; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D017384:Sequence Deletion; D050807:ets-Domain Protein Elk-1 / Q000737:chemistry* / Q000378:metabolism
chemical_list: D050807:ets-Domain Protein Elk-1; D004247:DNA; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease