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Noncysteinyl coordination to the [4Fe-4S]2+ cluster of the DNA repair adenine glycosylase MutY introduced via site-directed mutagenesis. Structural characterization of an unusual histidinyl-coordinated cluster.

Messick TE, Chmiel NH, Golinelli MP, Langer MR, Joshua-Tor L, David SS
Biochemistry 41 3931-42 (2002)
Cited: 22 times
EuropePMC logo PMID: 11900536

Abstract

The Escherichia coli DNA repair enzyme MutY plays an important role in the recognition and repair of 7,8-dihydro-8-oxo-2'-deoxyguanosine-2'-deoxyadenosine (OG*A) mismatches in DNA. MutY prevents DNA mutations caused by the misincorporation of A opposite OG by catalyzing the deglycosylation of the aberrant adenine. MutY is representative of a unique subfamily of DNA repair enzymes that also contain a [4Fe-4S]2+ cluster, which has been implicated in substrate recognition. Previously, we have used site-directed mutagenesis to individually replace the cysteine ligands to the [4Fe-4S]2+ cluster of E. coli MutY with serine, histidine, or alanine. These experiments suggested that histidine coordination to the iron-sulfur cluster may be accommodated in MutY at position 199. Purification and enzymatic analysis of C199H and C199S forms indicated that these forms behave nearly identical to the WT enzyme. Furthermore, introduction of the C199H mutation in a truncated form of MutY (C199HT) allowed for crystallization and structural characterization of the modified [4Fe-4S] cluster coordination. The C199HT structure showed that histidine coordinated to the iron cluster although comparison to the structure of the WT truncated enzyme indicated that the occupancy of iron at the modified position had been reduced to 60%. Electron paramagnetic resonance (EPR) spectroscopy on samples of C199HT indicates that a significant percentage (15-30%) of iron clusters were of the [3Fe-4S]1+ form. Oxidation of the C199HT enzyme with ferricyanide increases the amount of the 3Fe cluster by approximately 2-fold. Detailed kinetic analysis on samples containing a mixture of [3Fe-4S]1+ and [4Fe-4S]2+ forms indicated that the reactivity of the [3Fe-4S]1+ C199HT enzyme does not differ significantly from that of the WT truncated enzyme. The relative resistance of the [4Fe-4S]2+ cluster toward oxidation, as well as the retention of activity of the [3Fe-4S]1+ form, may be an important aspect of the role of MutY in repair of DNA damage resulting from oxidative stress.

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Reviews citing this publication (5)

  1. A role for iron-sulfur clusters in DNA repair. Lukianova OA, David SS. Curr Opin Chem Biol 9 145-151 (2005)
  2. DNA base repair--recognition and initiation of catalysis. Dalhus B, Laerdahl JK, Backe PH, Bjørås M. FEMS Microbiol Rev 33 1044-1078 (2009)
  3. Electrochemistry of nonconjugated proteins and glycoproteins. Toward sensors for biomedicine and glycomics. Paleček E, Tkáč J, Bartošík M, Bertók T, Ostatná V, Paleček J. Chem Rev 115 2045-2108 (2015)
  4. Repair of 8-oxoG:A mismatches by the MUTYH glycosylase: Mechanism, metals and medicine. Banda DM, Nuñez NN, Burnside MA, Bradshaw KM, David SS. Free Radic Biol Med 107 202-215 (2017)
  5. DNA repair glycosylases with a [4Fe-4S] cluster: a redox cofactor for DNA-mediated charge transport? Boal AK, Yavin E, Barton JK. J Inorg Biochem 101 1913-1921 (2007)

Articles citing this publication (15)

  1. DNA-mediated charge transport for DNA repair. Boon EM, Livingston AL, Chmiel NH, David SS, Barton JK. Proc Natl Acad Sci U S A 100 12543-12547 (2003)
  2. Protein-DNA charge transport: redox activation of a DNA repair protein by guanine radical. Yavin E, Boal AK, Stemp ED, Boon EM, Livingston AL, O'Shea VL, David SS, Barton JK. Proc Natl Acad Sci U S A 102 3546-3551 (2005)
  3. Insight into the functional consequences of inherited variants of the hMYH adenine glycosylase associated with colorectal cancer: complementation assays with hMYH variants and pre-steady-state kinetics of the corresponding mutated E.coli enzymes. Chmiel NH, Livingston AL, David SS. J Mol Biol 327 431-443 (2003)
  4. Molecular function of WhiB4/Rv3681c of Mycobacterium tuberculosis H37Rv: a [4Fe-4S] cluster co-ordinating protein disulphide reductase. Alam MS, Garg SK, Agrawal P. Mol Microbiol 63 1414-1431 (2007)
  5. MUTYH DNA glycosylase: the rationale for removing undamaged bases from the DNA. Markkanen E, Dorn J, Hübscher U. Front Genet 4 18 (2013)
  6. Mutants of the base excision repair glycosylase, endonuclease III: DNA charge transport as a first step in lesion detection. Romano CA, Sontz PA, Barton JK. Biochemistry 50 6133-6145 (2011)
  7. Essential role of the iron-sulfur cluster binding domain of the primase regulatory subunit Pri2 in DNA replication initiation. Liu L, Huang M. Protein Cell 6 194-210 (2015)
  8. An EPR/HYSCORE, Mössbauer, and resonance Raman study of the hydrogenase maturation enzyme HydF: a model for N-coordination to [4Fe-4S] clusters. Berggren G, Garcia-Serres R, Brazzolotto X, Clemancey M, Gambarelli S, Atta M, Latour JM, Hernández HL, Subramanian S, Johnson MK, Fontecave M. J Biol Inorg Chem 19 75-84 (2014)
  9. A unique uracil-DNA binding protein of the uracil DNA glycosylase superfamily. Sang PB, Srinath T, Patil AG, Woo EJ, Varshney U. Nucleic Acids Res 43 8452-8463 (2015)
  10. Synthetic analogues of [Fe4S4(Cys)3(His)] in hydrogenases and [Fe4S4(Cys)4] in HiPIP derived from all-ferric [Fe4S4{N(SiMe3)2}4]. Ohki Y, Tanifuji K, Yamada N, Imada M, Tajima T, Tatsumi K. Proc Natl Acad Sci U S A 108 12635-12640 (2011)
  11. Tridentate thiolate ligands: application to the synthesis of the site-differentiated [4Fe-4S] cluster having a hydrosulfide ligand at the unique iron center. Terada T, Wakimoto T, Nakamura T, Hirabayashi K, Tanaka K, Li J, Matsumoto T, Tatsumi K. Chem Asian J 7 920-929 (2012)
  12. Analysis of differences in oxygen sensitivity of Fe-S clusters. Bruska MK, Stiebritz MT, Reiher M. Dalton Trans 42 8729-8735 (2013)
  13. A comprehensive mechanistic model of iron metabolism in Saccharomyces cerevisiae. Lindahl PA. Metallomics 11 1779-1799 (2019)
  14. Dispensability of the [4Fe-4S] cluster in novel homologues of adenine glycosylase MutY. Trasviña-Arenas CH, Lopez-Castillo LM, Sanchez-Sandoval E, Brieba LG. FEBS J 283 521-540 (2016)
  15. UvrC Coordinates an O2-Sensitive [4Fe4S] Cofactor. Silva RMB, Grodick MA, Barton JK. J Am Chem Soc 142 10964-10977 (2020)


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