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Distinctive conformation of minor site-specific nuclear localization signals bound to importin-α.

Chang CW, Couñago RM, Williams SJ, Bodén M, Kobe B
Traffic 14 1144-54 (2013)
Related entries: 3zio, 3zip, 3ziq, 3zir

Cited: 38 times
EuropePMC logo PMID: 23910026

Abstract

Nuclear localization signals (NLSs) contain one or two clusters of basic residues and are recognized by the import receptor importin-α. There are two NLS-binding sites (major and minor) on importin-α and the major NLS-binding site is considered to be the primary binding site. Here, we used crystallographic and biochemical methods to investigate the binding between importin-α and predicted 'minor site-specific' NLSs: four peptide library-derived peptides, and the NLS from mouse RNA helicase II/Guα. The crystal structures reveal that these atypical NLSs indeed preferentially bind to the minor NLS-binding site. Unlike previously characterized NLSs, the C-terminal residues of these NLSs form an α-helical turn, stabilized by internal H-bond and cation-π interactions between the aromatic residues from the NLSs and the positively charged residues from importin-α. This helical turn sterically hinders binding at the major NLS-binding site, explaining the minor-site preference. Our data suggest the sequence RXXKR[K/X][F/Y/W]XXAF as the optimal minor NLS-binding site-specific motif, which may help identify novel proteins with atypical NLSs.

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  2. FlexPepDock lessons from CAPRI peptide-protein rounds and suggested new criteria for assessment of model quality and utility. Marcu O, Dodson EJ, Alam N, Sperber M, Kozakov D, Lensink MF, Schueler-Furman O. Proteins 85 445-462 (2017)
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  4. Comparative study of the interactions between fungal transcription factor nuclear localization sequences with mammalian and fungal importin-alpha. Bernardes NE, Fukuda CA, da Silva TD, de Oliveira HC, de Barros AC, Dreyer TR, Bertolini MC, Fontes MRM. Sci Rep 10 1458 (2020)
  5. Bioinformatics and Functional Analysis of a New Nuclear Localization Sequence of the Influenza A Virus Nucleoprotein. Nguyen NLT, Panté N. Cells 11 2957 (2022)


Reviews citing this publication (3)

  1. Structural Biology and Regulation of Protein Import into the Nucleus. Christie M, Chang CW, Róna G, Smith KM, Stewart AG, Takeda AA, Fontes MR, Stewart M, Vértessy BG, Forwood JK, Kobe B. J Mol Biol 428 2060-2090 (2016)
  2. Diversification of importin-α isoforms in cellular trafficking and disease states. Pumroy RA, Cingolani G. Biochem J 466 13-28 (2015)
  3. Factors influencing the nuclear targeting ability of nuclear localization signals. Sun Y, Xian L, Xing H, Yu J, Yang Z, Yang T, Yang L, Ding P. J Drug Target 24 927-933 (2016)

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  3. Addressing recent docking challenges: A hybrid strategy to integrate template-based and free protein-protein docking. Yan Y, Wen Z, Wang X, Huang SY. Proteins 85 497-512 (2017)
  4. Structure of importin-α bound to a non-classical nuclear localization signal of the influenza A virus nucleoprotein. Nakada R, Hirano H, Matsuura Y. Sci Rep 5 15055 (2015)
  5. Three-dimensional context rather than NLS amino acid sequence determines importin α subtype specificity for RCC1. Sankhala RS, Lokareddy RK, Begum S, Pumroy RA, Gillilan RE, Cingolani G. Nat Commun 8 979 (2017)
  6. Distinctive Properties of the Nuclear Localization Signals of Inner Nuclear Membrane Proteins Heh1 and Heh2. Lokareddy RK, Hapsari RA, van Rheenen M, Pumroy RA, Bhardwaj A, Steen A, Veenhoff LM, Cingolani G. Structure 23 1305-1316 (2015)
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  8. The truncated NLR protein TIR-NBS13 is a MOS6/IMPORTIN-α3 interaction partner required for plant immunity. Roth C, Lüdke D, Klenke M, Quathamer A, Valerius O, Braus GH, Wiermer M. Plant J 92 808-821 (2017)
  9. Structural characterisation of the nuclear import receptor importin alpha in complex with the bipartite NLS of Prp20. Roman N, Christie M, Swarbrick CM, Kobe B, Forwood JK. PLoS One 8 e82038 (2013)
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  11. Divergent Evolution of Nuclear Localization Signal Sequences in Herpesvirus Terminase Subunits. Sankhala RS, Lokareddy RK, Cingolani G. J Biol Chem 291 11420-11433 (2016)
  12. Differential recognition of canonical NF-κB dimers by Importin α3. Florio TJ, Lokareddy RK, Yeggoni DP, Sankhala RS, Ott CA, Gillilan RE, Cingolani G. Nat Commun 13 1207 (2022)
  13. DNA polymerase β contains a functional nuclear localization signal at its N-terminus. Kirby TW, Gassman NR, Smith CE, Zhao ML, Horton JK, Wilson SH, London RE. Nucleic Acids Res 45 1958-1970 (2017)
  14. PixelDB: Protein-peptide complexes annotated with structural conservation of the peptide binding mode. Frappier V, Duran M, Keating AE. Protein Sci 27 276-285 (2018)
  15. Design rules for selective binding of nuclear localization signals to minor site of importin α. Pang X, Zhou HX. PLoS One 9 e91025 (2014)
  16. Functional analysis of nuclear localization signals in VP1-2 homologues from all herpesvirus subfamilies. Hennig T, Abaitua F, O'Hare P. J Virol 88 5391-5405 (2014)
  17. The distribution of different classes of nuclear localization signals (NLSs) in diverse organisms and the utilization of the minor NLS-binding site inplantnuclear import factor importin-α. Chang CW, Couñago RM, Williams SJ, Boden M, Kobe B. Plant Signal Behav 8 e25976 (2013)
  18. Selective Targeting of the TPX2 Site of Importin-α Using Fragment-Based Ligand Design. Holvey RS, Valkov E, Neal D, Stewart M, Abell C. ChemMedChem 10 1232-1239 (2015)
  19. pyDock scoring for the new modeling challenges in docking: Protein-peptide, homo-multimers, and domain-domain interactions. Pallara C, Jiménez-García B, Romero M, Moal IH, Fernández-Recio J. Proteins 85 487-496 (2017)
  20. Nuclear Translocation Sequence and Region in Autographa californica Multiple Nucleopolyhedrovirus ME53 That Are Important for Optimal Baculovirus Production. Liu Y, de Jong J, Nagy É, Theilmann DA, Krell PJ. J Virol 90 3953-3965 (2016)
  21. Protein-protein and peptide-protein docking and refinement using ATTRACT in CAPRI. Schindler CE, Chauvot de Beauchêne I, de Vries SJ, Zacharias M. Proteins 85 391-398 (2017)
  22. Structural characterisation of TNRC6A nuclear localisation signal in complex with importin-alpha. Chaston JJ, Stewart AG, Christie M. PLoS One 12 e0183587 (2017)
  23. Human Enzyme PADI4 Binds to the Nuclear Carrier Importin α3. Neira JL, Rizzuti B, Abián O, Araujo-Abad S, Velázquez-Campoy A, de Juan Romero C. Cells 11 2166 (2022)
  24. Structural and calorimetric studies demonstrate that the hepatocyte nuclear factor 1β (HNF1β) transcription factor is imported into the nucleus via a monopartite NLS sequence. Wiedmann MM, Aibara S, Spring DR, Stewart M, Brenton JD. J Struct Biol 195 273-281 (2016)
  25. Structural insights into the nuclear import of the histone acetyltransferase males-absent-on-the-first by importin α1. Zheng W, Wang R, Liu X, Tian S, Yao B, Chen A, Jin S, Li Y. Traffic 19 19-28 (2018)
  26. Baculovirus LEF-11 nuclear localization signal is important for viral DNA replication. Chen T, Dong Z, Hu N, Hu Z, Dong F, Jiang Y, Li J, Chen P, Lu C, Pan M. Virus Res 238 133-140 (2017)
  27. Distinctive Conformation of Minor Site-Specific Nuclear Localization Signals Bound to Importin-α. Chang CW, Couñago RM, Williams SJ, Bodén M, Kobe B. Traffic 17 704 (2016)
  28. Henipavirus Matrix Protein Employs a Non-Classical Nuclear Localization Signal Binding Mechanism. Donnelly CM, Vogel OA, Edwards MR, Taylor PE, Roby JA, Forwood JK, Basler CF. Viruses 15 1302 (2023)
  29. MOS6 and TN13 in plant immunity. Lüdke D, Roth C, Hartken D, Wiermer M. Plant Signal Behav 13 e1454816 (2018)
  30. Recognition motifs for importin 4 [(L)PPRS(G/P)P] and importin 5 [KP(K/Y)LV] binding, identified by bio-informatic simulation and experimental in vitro validation. Panagiotopoulos AA, Kalyvianaki K, Tsodoulou PK, Darivianaki MN, Dellis D, Notas G, Daskalakis V, Theodoropoulos PA, Panagiotidis CΑ, Castanas E, Kampa M. Comput Struct Biotechnol J 20 5952-5961 (2022)


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