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Quasi-equivalence in site-specific recombinase structure and function: crystal structure and activity of trimeric Cre recombinase bound to a three-way Lox DNA junction.

Woods KC, Martin SS, Chu VC, Baldwin EP
J Mol Biol 313 49-69 (2001)
Cited: 34 times
EuropePMC logo PMID: 11601846

Abstract

The crystal structure of a novel Cre-Lox synapse was solved using phases from multiple isomorphous replacement and anomalous scattering, and refined to 2.05 A resolution. In this complex, a symmetric protein trimer is bound to a Y-shaped three-way DNA junction, a marked departure from the pseudo-4-fold symmetrical tetramer associated with Cre-mediated LoxP recombination. The three-way DNA junction was accommodated by a simple kink without significant distortion of the adjoining DNA duplexes. Although the mean angle between DNA arms in the Y and X structures was similar, adjacent Cre trimer subunits rotated 29 degrees relative to those in the tetramers. This rotation was accommodated at the protein-protein and DNA-DNA interfaces by interactions that are "quasi-equivalent" to those in the tetramer, analogous to packing differences of chemically identical viral subunits at non-equivalent positions in icosahedral capsids. This structural quasi-equivalence extends to function as Cre can bind to, cleave and perform strand transfer with a three-way Lox substrate. The structure explains the dual recognition of three and four-way junctions by site-specific recombinases as being due to shared structural features between the differently branched substrates and plasticity of the protein-protein interfaces. To our knowledge, this is the first direct demonstration of quasi-equivalence in both the assembly and function of an oligomeric enzyme.

Reviews - 1drg mentioned but not cited (1)

  1. Supramolecular DNA Three-Way Junction Motifs With a Bridging Metal Center. Takezawa Y, Shionoya M. Front Chem 7 925 (2019)

Articles - 1drg mentioned but not cited (1)

  1. Conservation of structure and function among tyrosine recombinases: homology-based modeling of the lambda integrase core-binding domain. Swalla BM, Gumport RI, Gardner JF. Nucleic Acids Res 31 805-818 (2003)


Reviews citing this publication (5)

  1. Mechanisms of site-specific recombination. Grindley ND, Whiteson KL, Rice PA. Annu Rev Biochem 75 567-605 (2006)
  2. DNA architecture: from G to Z. Phan AT, Kuryavyi V, Patel DJ. Curr Opin Struct Biol 16 288-298 (2006)
  3. New insight into site-specific recombination from Flp recombinase-DNA structures. Chen Y, Rice PA. Annu Rev Biophys Biomol Struct 32 135-159 (2003)
  4. Cre-loxP biochemistry. Ghosh K, Van Duyne GD. Methods 28 374-383 (2002)
  5. DNA manipulators: caught in the act. Changela A, Perry K, Taneja B, Mondragón A. Curr Opin Struct Biol 13 15-22 (2003)

Articles citing this publication (27)

  1. Molecular recognition of a three-way DNA junction by a metallosupramolecular helicate. Oleksy A, Blanco AG, Boer R, Usón I, Aymamí J, Rodger A, Hannon MJ, Coll M. Angew Chem Int Ed Engl 45 1227-1231 (2006)
  2. DNA conformations and their sequence preferences. Svozil D, Kalina J, Omelka M, Schneider B. Nucleic Acids Res 36 3690-3706 (2008)
  3. The order of strand exchanges in Cre-LoxP recombination and its basis suggested by the crystal structure of a Cre-LoxP Holliday junction complex. Martin SS, Pulido E, Chu VC, Lechner TS, Baldwin EP. J Mol Biol 319 107-127 (2002)
  4. Crystal structure of a wild-type Cre recombinase-loxP synapse reveals a novel spacer conformation suggesting an alternative mechanism for DNA cleavage activation. Ennifar E, Meyer JE, Buchholz F, Stewart AF, Suck D. Nucleic Acids Res 31 5449-5460 (2003)
  5. Structural plasticity of the Flp-Holliday junction complex. Conway AB, Chen Y, Rice PA. J Mol Biol 326 425-434 (2003)
  6. DNA topology and geometry in Flp and Cre recombination. Vetcher AA, Lushnikov AY, Navarra-Madsen J, Scharein RG, Lyubchenko YL, Darcy IK, Levene SD. J Mol Biol 357 1089-1104 (2006)
  7. Recognition of nucleic acid junctions using triptycene-based molecules. Barros SA, Chenoweth DM. Angew Chem Int Ed Engl 53 13746-13750 (2014)
  8. The role of the conserved Trp330 in Flp-mediated recombination. Functional and structural analysis. Chen Y, Rice PA. J Biol Chem 278 24800-24807 (2003)
  9. A specificity switch in selected cre recombinase variants is mediated by macromolecular plasticity and water. Baldwin EP, Martin SS, Abel J, Gelato KA, Kim H, Schultz PG, Santoro SW. Chem Biol 10 1085-1094 (2003)
  10. Modulation of the active complex assembly and turnover rate by protein-DNA interactions in Cre-LoxP recombination. Martin SS, Chu VC, Baldwin E. Biochemistry 42 6814-6826 (2003)
  11. Reversed DNA strand cleavage specificity in initiation of Cre-LoxP recombination induced by the His289Ala active-site substitution. Gelato KA, Martin SS, Baldwin EP. J Mol Biol 354 233-245 (2005)
  12. Organization of DNA partners and strand exchange mechanisms during Flp site-specific recombination analyzed by difference topology, single molecule FRET and single molecule TPM. Ma CH, Liu YT, Savva CG, Rowley PA, Cannon B, Fan HF, Russell R, Holzenburg A, Jayaram M. J Mol Biol 426 793-815 (2014)
  13. Reactions of Cre with methylphosphonate DNA: similarities and contrasts with Flp and vaccinia topoisomerase. Ma CH, Kachroo AH, Macieszak A, Chen TY, Guga P, Jayaram M. PLoS One 4 e7248 (2009)
  14. Triptycene-based small molecules modulate (CAG)·(CTG) repeat junctions. Barros SA, Chenoweth DM. Chem Sci 6 4752-4755 (2015)
  15. Supramolecular Recognition of Three Way Junction DNA by a Cationic Calix[3]carbazole. Yang Z, Chen Y, Li G, Tian Z, Zhao L, Wu X, Ma Q, Liu M, Yang P. Chemistry 24 6087-6093 (2018)
  16. Crystal structure of Thermoplasma acidophilum XerA recombinase shows large C-shape clamp conformation and cis-cleavage mode for nucleophilic tyrosine. Jo CH, Kim J, Han AR, Park SY, Hwang KY, Nam KH. FEBS Lett 590 848-856 (2016)
  17. Efficient photoactivatable Dre recombinase for cell type-specific spatiotemporal control of genome engineering in the mouse. Li H, Zhang Q, Gu Y, Wu Y, Wang Y, Wang L, Feng S, Hu Y, Zheng Y, Li Y, Ye H, Zhou B, Lin L, Liu M, Yang H, Li D. Proc Natl Acad Sci U S A 117 33426-33435 (2020)
  18. Spatially directed assembly of a heterotetrameric Cre-Lox synapse restricts recombination specificity. Gelato KA, Martin SS, Liu PH, Saunders AA, Baldwin EP. J Mol Biol 378 653-665 (2008)
  19. Multiple levels of affinity-dependent DNA discrimination in Cre-LoxP recombination. Gelato KA, Martin SS, Wong S, Baldwin EP. Biochemistry 45 12216-12226 (2006)
  20. Mechanisms of Cre recombinase synaptic complex assembly and activation illuminated by Cryo-EM. Stachowski K, Norris AS, Potter D, Wysocki VH, Foster MP. Nucleic Acids Res 50 1753-1769 (2022)
  21. Mutational analysis and homology-based modeling of the IntDOT core-binding domain. Malanowska K, Cioni J, Swalla BM, Salyers A, Gardner JF. J Bacteriol 191 2330-2339 (2009)
  22. Restoration of catalytic functions in Cre recombinase mutants by electrostatic compensation between active site and DNA substrate. Kachroo AH, Ma CH, Rowley PA, Maciaszek AD, Guga P, Jayaram M. Nucleic Acids Res 38 6589-6601 (2010)
  23. Bridgehead-Substituted Triptycenes for Discovery of Nucleic Acid Junction Binders. Barros SA, Yoon I, Suh SE, Chenoweth DM. Org Lett 18 2423-2426 (2016)
  24. Loop-closure kinetics reveal a stable, right-handed DNA intermediate in Cre recombination. Shoura MJ, Giovan SM, Vetcher AA, Ziraldo R, Hanke A, Levene SD. Nucleic Acids Res 48 4371-4381 (2020)
  25. Vanadate-based transition-state analog inhibitors of Cre-LoxP recombination. Martin SS, Wachi S, Baldwin EP. Biochem Biophys Res Commun 308 529-534 (2003)
  26. A copper(ii) peptide helicate selectively cleaves DNA replication foci in mammalian cells. Alcalde-Ordóñez A, Barreiro-Piñeiro N, McGorman B, Gómez-González J, Bouzada D, Rivadulla F, Vázquez ME, Kellett A, Martínez-Costas J, López MV. Chem Sci 14 14082-14091 (2023)
  27. Organometallic Pillarplexes That Bind DNA 4-Way Holliday Junctions and Forks. Craig JS, Melidis L, Williams HD, Dettmer SJ, Heidecker AA, Altmann PJ, Guan S, Campbell C, Browning DF, Sigel RKO, Johannsen S, Egan RT, Aikman B, Casini A, Pöthig A, Hannon MJ. J Am Chem Soc 145 13570-13580 (2023)


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