10sm
Importin-9 bound to ETS homologous factor (EHF)
Structural highlights
FunctionEHF_HUMAN Transcriptional activator that may play a role in regulating epithelial cell differentiation and proliferation. May act as a repressor for a specific subset of ETS/AP-1-responsive genes and as a modulator of the nuclear response to mitogen-activated protein kinase signaling cascades. Binds to DNA sequences containing the consensus nucleotide core sequence GGAA. Involved in regulation of TNFRSF10B/DR5 expression through Ets-binding sequences on the TNFRSF10B/DR5 promoter. May contribute to development and carcinogenesis by acting as a tumor suppressor gene or anti-oncogene.[1] [2] [3] [4] [5] Publication Abstract from PubMedProtein trafficking between the cytoplasm and the nucleus is a fundamental process in eukaryotic cell biology. While linear nuclear localization signals (NLSs) are well characterized, many nuclear proteins lack a predictable NLS. Here, we identify the ETS domain, a DNA-binding winged-helix fold, from ETS family transcription factors as a structure-encoded NLS. We show that ETS domains mediate nuclear import through direct nanomolar affinity recognition by IPO9. Cryo-electron microscopy analysis of the EHF:IPO9 complex reveals that the IPO9 wraps around the ETS domain and engages structural features throughout the winged-helix fold. Biochemical studies demonstrate that the ETS domain DNA-binding helix is critical for importin recognition and for NLS activity in mammalian cells. Comparison of IPO9 bound to EHF and the histone H2A:H2B dimer reveals distinct interaction hotspots, illustrating how IPO9 employs unique combinatorial binding surfaces to accommodate structurally diverse cargos. These findings define a unique class of globular NLSs and highlight the adaptability of importins in recognizing distinct protein folds. Importin-9 recognizes the winged-helix fold of ETS transcription factors to mediate nuclear import.,McConville M, Lankford K, Bernardes NE, Walterscheid A, Valadez C, Niesman A, Chook YM, Liszczak G Proc Natl Acad Sci U S A. 2026 May 5;123(18):e2536763123. doi: , 10.1073/pnas.2536763123. Epub 2026 May 1. PMID:42066049[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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