4rxh | pdb_00004rxh
Crystal Structure of Importin-alpha from Neurospora crassa complexed with SV40NLS
Structural highlights
Function[LT_SV40] Isoform large T antigen is a key early protein essential for both driving viral replication and inducing cellular transformation. Plays a role in viral genome replication by driving entry of quiescent cells into the cell cycle and by autoregulating the synthesis of viral early mRNA. Displays highly oncogenic activities by corrupting the host cellular checkpoint mechanisms that guard cell division and the transcription, replication, and repair of DNA. Participates in the modulation of cellular gene expression preceeding viral DNA replication. This step involves binding to host key cell cycle regulators retinoblastoma protein RB1/pRb and TP53. Induces the disassembly of host E2F1 transcription factors from RB1, thus promoting transcriptional activation of E2F1-regulated S-phase genes. Inhibits host TP53 binding to DNA, abrogating the ability of TP53 to stimulate gene expression. Plays the role of a TFIID-associated factor (TAF) in transcription initiation for all three RNA polymerases, by stabilizing the TBP-TFIIA complex on promoters. Initiates viral DNA replication and unwinding via interactions with the viral origin of replication. Binds two adjacent sites in the SV40 origin. The replication fork movement is facilitated by Large T antigen helicase activity. Activates the transcription of viral late mRNA, through host TBP and TFIIA stabilization. Interferes with histone deacetylation mediated by HDAC1, leading to activation of transcription. May inactivate the growth-suppressing properties of the E3 ubiquitin ligase CUL7.[1] [2] [3] [4] [5] [6] [7] Isoform 17kT antigen targets host RBL2 for degradation and promotes cell proliferation. Transactivates host cyclin A promoter through its J domain.[8] [9] [10] [11] [12] [13] [14] Publication Abstract from PubMedNeurospora crassa is a filamentous fungus that has been extensively studied as a model organism for eukaryotic biology, providing fundamental insights into cellular processes such as cell signaling, growth and differentiation. To advance in the study of this multicellular organism, an understanding of the specific mechanisms for protein transport into the cell nucleus is essential. Importin-alpha (Imp-alpha) is the receptor for cargo proteins that contain specific nuclear localization signals (NLSs) that play a key role in the classical nuclear import pathway. Structures of Imp-alpha from different organisms (yeast, rice, mouse, and human) have been determined, revealing that this receptor possesses a conserved structural scaffold. However, recent studies have demonstrated that the Impalpha mechanism of action may vary significantly for different organisms or for different isoforms from the same organism. Therefore, structural, functional, and biophysical characterization of different Impalpha proteins is necessary to understand the selectivity of nuclear transport. Here, we determined the first crystal structure of an Impalpha from a filamentous fungus which is also the highest resolution Impalpha structure already solved to date (1.75 A). In addition, we performed calorimetric analysis to determine the affinity and thermodynamic parameters of the interaction between Imp-alpha and the classical SV40 NLS peptide. The comparison of these data with previous studies on Impalpha proteins led us to demonstrate that N. crassa Imp-alpha possess specific features that are distinct from mammalian Imp-alpha but exhibit important similarities to rice Imp-alpha, particularly at the minor NLS binding site. Structure of Importin-alpha from a Filamentous Fungus in Complex with a Classical Nuclear Localization Signal.,Bernardes NE, Takeda AA, Dreyer TR, Freitas FZ, Bertolini MC, Fontes MR PLoS One. 2015 Jun 19;10(6):e0128687. doi: 10.1371/journal.pone.0128687., eCollection 2015. PMID:26091498[15] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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