Role of a tryptophan anchor in human topoisomerase I structure, function and inhibition.

The Biochemical Journal
Gary S Laco, Yves Pommier

Abstract

Human Top1 (topoisomerase I) relaxes supercoiled DNA during cell division and transcription. Top1 is composed of 765 amino acids and contains an unstructured N-terminal domain of 200 amino acids, and a structured functional domain of 565 amino acids that binds and relaxes supercoiled DNA. In the present study we examined the region spanning the junction of the N-terminal domain and functional domain (junction region). Analysis of several published Top1 structures revealed that three tryptophan residues formed a network of aromatic stacking interactions and electrostatic interactions that anchored the N-terminus of the functional domain to sub-domains containing the nose cone and active site. Mutation of the three tryptophan residues (Trp(203)/Trp(205)/Trp(206)) to an alanine residue, either individually or together, in silico revealed that the individual tryptophan residue's contribution to the tryptophan 'anchor' was additive. When the three tryptophan residues were mutated to alanine in vitro, the resulting mutant Top1 differed from wild-type Top1 in that it lacked processivity, exhibited resistance to camptothecin and was inactivated by urea. The results indicated that the tryptophan anchor stabilized the N-terminus of the f...Continue Reading

References

Apr 1, 1988·Proceedings of the National Academy of Sciences of the United States of America·P D'ArpaW C Earnshaw
Jul 1, 1985·Proceedings of the National Academy of Sciences of the United States of America·C ThrashR Sternglanz
Jan 1, 1972·Proceedings of the National Academy of Sciences of the United States of America·J J Champoux, R Dulbecco
Jan 1, 1994·Annual Review of Pharmacology and Toxicology·A Y Chen, L F Liu
Mar 29, 1996·The Journal of Biological Chemistry·L StewartJ J Champoux
Jan 1, 1996·Annual Review of Biochemistry·J C Wang
Dec 1, 1996·Protein Science : a Publication of the Protein Society·G S PrasadC D Stout
Mar 21, 1998·Science·L StewartJ J Champoux
May 22, 1998·Progress in Nucleic Acid Research and Molecular Biology·J J Champoux
Sep 28, 1998·Biochimica Et Biophysica Acta·Y PommierD Strumberg
Feb 17, 1999·Proceedings of the National Academy of Sciences of the United States of America·A KrammerV Vogel
Jul 2, 1999·Journal of Molecular Biology·J TsaiM Gerstein
Sep 1, 2000·The Journal of Biological Chemistry·T K EdwardsE H Rubin
Sep 20, 2000·Proceedings of the National Academy of Sciences of the United States of America·Y PommierD M Jerina
Oct 4, 2000·The Journal of Biological Chemistry·Y Y MoW T Beck
Apr 3, 2001·The Journal of Biological Chemistry·M LisbyB R Knudsen
May 2, 2001·Proceedings of the National Academy of Sciences of the United States of America·D CraigV Vogel
Jun 8, 2001·Annual Review of Biochemistry·J J Champoux
Jan 24, 2002·Proceedings of the National Academy of Sciences of the United States of America·Yinghui MaoMark T Muller
Feb 7, 2002·Proceedings of the National Academy of Sciences of the United States of America·Berit Olsen Krogh, Stewart Shuman
Sep 5, 2002·Proceedings of the National Academy of Sciences of the United States of America·Diem-Thu Thieu LesherMatthew R Redinbo
Nov 12, 2002·Proceedings of the National Academy of Sciences of the United States of America·Bart L StakerLance Stewart
Apr 19, 2003·Proceedings of the National Academy of Sciences of the United States of America·Brian J Bennion, Valerie Daggett
Dec 5, 2003·Nucleic Acids Research·Morten O ChristensenChristian Mielke
Jan 27, 2004·Journal of Molecular Biology·Rikke From FrøhlichBirgitta Ruth Knudsen
Dec 22, 2005·The Journal of Biological Chemistry·Asmita PatelAlfonso Mondragón
May 13, 2006·Annual Review of Biophysics and Biomolecular Structure·Viola Vogel
Apr 19, 2007·Nucleic Acids Research·Giovanni ChillemiAlessandro Desideri

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Citations

Feb 11, 2012·Biochemistry·Takao IshikawaKrzysztof Staron
Sep 20, 2012·Proceedings of the National Academy of Sciences of the United States of America·Yeonee SeolKeir C Neuman
Nov 4, 2010·Amino Acids·Oscar VassalloAlessandro Desideri
Mar 17, 2011·Biomaterials·Yi-An ChenTzong-Yueh Chen
Aug 13, 2013·Journal of Molecular Graphics & Modelling·Neslihan UcuncuogluLevent Sari
Aug 1, 2012·Biochimica Et Biophysica Acta·M Sameer Al-Abdul-WahidBryan A Stewart
Sep 2, 2009·Nucleic Acids Research·Ilaria Dalla RosaMorten O Christensen
Jul 30, 2010·Biomedical Papers of the Medical Faculty of the University Palacký, Olomouc, Czechoslovakia·Petra JancovaEva Anzenbacherova
Mar 22, 2015·The Journal of Biological Chemistry·Christine M WrightMary-Ann Bjornsti
May 21, 2020·Molecular Cancer Therapeutics·Laetitia MarziYves Pommier

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